Therapeutic uses of relacorilant, a heteroaryl-ketone fused azadecalin glucocorticoid receptor modulator

ABSTRACT

Methods and compositions are disclosed for diagnosing a patient suspected of suffering from, and for treating a patient suffering from, a disorder such as hypercortisolemia, metabolic syndrome, pre-diabetes, diabetes, Cushing&#39;s syndrome, Cushing&#39;s Disease, hyperglycemia secondary to hypercortisolemia, a liver disease, a cardiac disorder, high blood pressure, a blood clotting disorder, a cancer, a psychological disorder, weight gain, a disorder of glucose control, a bone disorder (e.g., osteoporosis), hypogonadism, pseudoacromegaly, pituitary tumors, functional hypercortisolism, ACTH secreting tumors, peripheral neuropathy, dyslipidemia and other disorders.The methods and compositions include administration of a heteroaryl-ketone fused azadecalin glucocorticoid receptor modulator (GRM). The preferred heteroaryl-ketone fused azadecalin GRM is relacorilant ((R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone). In some cases, the GRM (e.g., relacorilant) is orally administered. In some cases, the GRM (e.g., relacorilant) is orally administered without food.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.16/797,421, filed Feb. 21, 2020, which claims, under 35 U.S.C. § 119(e),priority to and the benefit of U.S. Provisional Patent Application Ser.No. 62/809,327, filed Feb. 22, 2019; U.S. Provisional Patent ApplicationSer. No. 62/814,441, filed Mar. 6, 2019; and U.S. Provisional PatentApplication Ser. No. 62/833,517, filed Apr. 12, 2019, the entirecontents of all of which applications are hereby incorporated byreference in their entireties.

BACKGROUND

Cortisol is a glucocorticoid (GC) hormone that binds to a glucocorticoidreceptor. Cortisol acts by binding to glucocorticoid receptor (GR) typeII, also referred to as the cortisol receptor, an intracellular receptorwhich specifically binds to cortisol and/or cortisol analogs such asdexamethasone (See, e.g., Turner & Muller, J. Mol. Endocrinol.35(2):283-292 (2005)). The term GR includes isoforms of GR, recombinantGR and mutated GR. Another glucocorticoid receptor, the type I GR, alsotermed the “mineralocorticoid receptor (MR)” mediates the response toaldosterone.

Cortisol is produced in the adrenal glands; excess cortisol may becaused by adrenal abnormalities (e.g., an adrenal tumor). The excesscortisol may be caused by excess adrenocorticotrophic hormone (ACTH)release from the pituitary gland acting on the adrenal glands to producethe excess cortisol. Cortisol excess may be termed “hypercortisolemia”or “hypercortisolism”. Patients suffering from hypercortisolemia oftenalso exhibit excess blood glucose (hyperglycemia), may suffer from lowpotassium (hypokalemia), high blood pressure, cardiac disorders, orother disorders. Excess cortisol (which leads to excess activation of GRtype II) characterizes and causes Cushing's syndrome, a debilitatingchronic disease caused by high levels of cortisol, and characterized byhigh blood sugar, high blood pressure, disorders of the heart rhythm,weight gain (including a characteristic “hump” on the neck or back),hirsuteness, depression, and other symptoms.

When excess pituitary ACTH release causes the excess cortisol, thedisorder is termed “Cushing's Disease”. Such excess pituitary ACTHrelease is typically caused by a pituitary tumor. First-line treatmentfor Cushing's Disease involves surgery to remove the pituitary tumor;however, in many cases not all of the tumor is able to be resected(e.g., if the tumor has invaded cranial regions outside the sellaturcica, or has invaded bone, or for other reasons), or it may growback, or may have metastasized (more often for non-pituitary (ectopic)tumors than for pituitary tumors). In some cases, radiation treatment isapplied following surgery. Conventional chemotherapy treatment oftenused for other tumors may be inapplicable for pituitary tumors, or maynot be suitable for patients suffering from pituitary tumors. Medicaltreatment to reduce cortisol production, or to block the effects ofcortisol (e.g., mifepristone (prescribed as KORLYM®)) is oftenadministered, particularly when symptoms persist following surgery.Radiation and standard chemotherapy may have severe side-effects, whichmay make them unsuitable for Cushing's patients. Thus, medical (i.e.,non-surgical) treatments for pituitary tumors which cause Cushing'sDisease are needed, and improved treatments would be helpful.

Patients suffering from other disorders may also exhibit excesscortisol, and excess cortisol may be a cause of such disorders. Forexample, patients suffering from psychotic major depression typicallyexhibit excess cortisol. However, methods and compositions effective forreducing the effects of cortisol, and particularly for reducing theeffects of excess cortisol, remain lacking.

SUMMARY

Disclosed herein are novel methods for treating a variety of disordersand diseases related to, or caused by, cortisol excess(hypercortisolemia or hypercortisolism), and for treating a variety ofdisorders and diseases which may be treated or symptoms ameliorated byreducing the effects or action of cortisol. Such diseases and disordersmay include, without limitation, Cushing's syndrome, Cushing's Disease,hyperglycemia secondary to hypercortisolemia, liver diseases (e.g.,fatty liver disease, non-alcoholic fatty liver disease (NAFLD),non-alcoholic steatohepatitis (NASH), alcoholic liver diseases, liverfibrosis, and other liver disorders), cardiac disorders (including,e.g., prolonged Q-T interval or other disorder of the heart rhythm),high blood pressure, hypercoagulopathy, cancers, bone disorders, bloodclotting disorders, psychological disorders, weight gain (includingweight gain due to antipsychotic medication), metabolic syndrome,pre-diabetes or diabetes, osteoporosis, hypogonadism, pseudoacromegaly,pituitary tumors, functional hypercortisolism, ACTH secreting tumors,peripheral neuropathy, dyslipidemia, and other diseases and disorders.Cortisol excess may also be found, for example, in patients withmetabolic syndrome, pre-diabetes or diabetes; or may also be found, forexample, in patients with liver disorders, such as, e.g., fatty liverdisease, non-alcoholic fatty liver disease (NAFLD), non-alcoholicsteatohepatitis (NASH), alcoholic liver diseases, liver fibrosis, andother liver disorders. The methods may include immunotherapy treatments.Reducing the effects of excess cortisol may improve the quality of lifeof a patient suffering from excess cortisol or its effects. Reducing theeffects of excess cortisol may improve the psychological status of apatient suffering from excess cortisol or its effects.

The methods comprise administering to the subject an effective amount ofa glucocorticoid receptor modulator (GRM) to reduce the effects of suchcortisol excess, and, in embodiments, comprise administering to thesubject an effective amount of a GRM along with another treatment (e.g.,another pharmaceutical composition, or surgery, or radiation, orpsychotherapy, or other treatment). In embodiments, the GRM is anonsteroidal GRM. In embodiments, the GRM is a nonsteroidal selectiveGRM. In embodiments, the GRM is a nonsteroidal heteroaryl-ketone fusedazadecalin selective GRM compound or a nonsteroidal octahydro fusedazadecalin selective GRM compound. In preferred embodiments, the GRM isthe nonsteroidal heteroaryl-ketone fused azadecalin selective GRMcompound having the chemical name(R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,termed “relacorilant”, having the formula

In embodiments, the methods disclosed herein include administration of aGRM, such as the heteroaryl-ketone fused azadecalin GRM relacorilant, toa patient in need of such treatment, to treat a disorder selected fromCushing's syndrome; Cushing's Disease; hyperglycemia secondary tohypercortisolemia; metabolic syndrome, pre-diabetes, or diabetes; aliver disease (e.g., fatty liver disease, non-alcoholic fatty liverdisease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liverdiseases, liver fibrosis, and other liver disorders); a cardiac disorder(including, e.g., prolonged Q-T interval or other disorder of the heartrhythm, with or without Left Ventricular Hypertrophy (LVH)); high bloodpressure; cancer; a psychological disorder (e.g., depression, such aspsychotic major depression); weight gain (including weight gain due toantipsychotic medication), and other diseases and disorders. A GRM, suchas relacorilant, may be administered to a patient as a monotherapy; and,in embodiments, a GRM, such as relacorilant, may be administered to apatient along with another treatment. The GRM may be administeredbefore, or after, or along with, or any combination thereof, anothertreatment. In addition, the methods disclosed herein includeadministration of a GRM, such as relacorilant, to a patient in need ofdiagnosis, to diagnose a disorder such as, e.g., Cushing's Disease.

In some cases, the GRM (e.g., relacorilant) is orally administered. Inembodiments, the GRM is administered with food. In embodiments, the GRMis administered to a patient who is fasting. In some cases, the GRM(e.g., a relacorilant) is administered with at least one pharmaceuticalagent. In some cases, the GRM (e.g., a relacorilant) is administeredafter the subject or patient has been administered at least one otherpharmaceutical agent. In some cases, the GRM (e.g., a relacorilant) isadministered before the subject or patient is administered at least oneother pharmaceutical agent. In some cases, the GRM (e.g., arelacorilant) is administered to a subject after the subject or patienthas undergone surgery. In some cases, the GRM (e.g., a relacorilant) isadministered to a subject before the subject or patient undergoessurgery.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 Patients achieving clinically meaningful reductions in HbA1c,2-hour oGTT or use of antidiabetic medications.

FIG. 2 Patients achieving clinically meaningful improvements inhypertension (high blood pressure).

FIG. 3 Relacorilant effects on Coagulation: There is a high risk ofthrombotic events in patients with Cushing's syndrome; Cushing'ssyndrome patients treated with relacorilant showed improvement incoagulation factors. This result indicates that relacorilant may beuseful to improve pre-operative coagulation control (before surgery forCushing's syndrome) in Cushing's syndrome patients at high risk ofthrombotic events.

DETAILED DESCRIPTION

Introduction

The methods disclosed herein can be used to treat a patient sufferingfrom a disorder by administering an effective amount of a glucocorticoidreceptor modulator (GRM), such as a selective glucocorticoid receptormodulator (SGRM), which in preferred embodiments is relacorilant (whichmay also be referred to as “RELA”). In embodiments, the methodsdisclosed herein include administration of a GRM, such as relacorilant,to a patient in need of such treatment, to treat a disorder selectedfrom Cushing's syndrome; Cushing's Disease; hyperglycemia secondary tohypercortisolemia; metabolic syndrome, pre-diabetes, or diabetes; aliver disease (e.g., fatty liver disease, non-alcoholic fatty liverdisease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liverdiseases, liver fibrosis, and other liver disorders); a cardiac disorder(including, e.g., prolonged Q-T interval or other disorder of the heartrhythm, with or without Left Ventricular Hypertrophy (LVH)); high bloodpressure; hypercoagulopathy; cancer; a psychological disorder (e.g.,depression, such as psychotic major depression); weight gain (includingweight gain due to antipsychotic medication); a bone disorder; a blooddisorder, such as a blood clotting disorder; osteoporosis, hypogonadism,pseudoacromegaly, pituitary tumors, functional hypercortisolism, ACTHsecreting tumors, peripheral neuropathy, dyslipidemia; and otherdiseases and disorders. A GRM or SGRM, such as relacorilant, may beadministered with an immunotherapy agent, such as a checkpointinhibitor, or other pharmaceutical agent. The methods disclosed hereincan be used to treat a patient suffering from any disorder indicated bythe results disclosed in Table 1. The methods disclosed herein can beused to normalize, in a patient, any diagnostic result indicated by theresults disclosed in Table 1.

The methods disclosed herein comprising administering a GRM, such asrelacorilant, can be used to diagnose a patient suspected of sufferingfrom a disorder selected from Cushing's syndrome; Cushing's Disease;hyperglycemia secondary to hypercortisolemia; metabolic syndrome,pre-diabetes, or diabetes; a liver disease (e.g., fatty liver disease,non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis(NASH), alcoholic liver diseases, liver fibrosis, and other liverdisorders); a cardiac disorder (including, e.g., prolonged Q-T intervalor other disorder of the heart rhythm, with or without Left VentricularHypertrophy (LVH)); high blood pressure; hypercoagulopathy; cancer; apsychological disorder (e.g., depression, such as psychotic majordepression); weight gain (including weight gain due to antipsychoticmedication); a bone disorder; a blood clotting disorder; and otherdiseases and disorders. The methods disclosed herein comprisingadministering a GRM, such as relacorilant, can be used to improve thequality of life of a patient. The methods disclosed herein comprisingadministering a GRM, such as relacorilant, can be used to diagnose apatient suspected of suffering from any disorder indicated by theresults disclosed in Table 1.

A GRM or SGRM, such as relacorilant, may be administered to a patient asa monotherapy; and, in embodiments, a GRM, such as relacorilant, may beadministered to a patient along with another treatment. The GRM may beadministered before, or after, or along with, or any combinationthereof, another treatment. In addition, the methods disclosed hereininclude administration of a GRM, such as relacorilant, to a patient inneed of diagnosis, to diagnose a disorder such as, e.g., Cushing'sDisease.

In embodiments, the GRM is a nonsteroidal GRM.

In some cases, the GRM (e.g., a SGRM) is a nonsteroidal compoundcomprising a heteroaryl ketone fused azadecalin structure. In somecases, the heteroaryl ketone fused azadecalin compound has the formula:

wherein R¹ is a heteroaryl ring having from 5 to 6 ring members and from1 to 4 heteroatoms each independently selected from the group consistingof N, O and S, optionally substituted with 1-4 groups each independentlyselected from R^(1a); each R^(1a) is independently selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, CN, N-oxide, C₃₋₈ cycloalkyl, and C₃₋₈heterocycloalkyl; ring J is selected from the group consisting of acycloalkyl ring, a heterocycloalkyl ring, an aryl ring and a heteroarylring, wherein the heterocycloalkyl and heteroaryl rings have from 5 to 6ring members and from 1 to 4 heteroatoms each independently selectedfrom the group consisting of N, O and S; each R² is independentlyselected from the group consisting of hydrogen, C₁₋₆ alkyl, halogen,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkyl-C₁₋₆ alkoxy,CN, OH, NR^(2a)R^(2b), C(O)R^(2a), C(O)OR^(2a), C(O)NR^(2a)R^(2b),SR^(2a), S(O)R^(2a), S(O)₂R^(2a), C₃₋₈ cycloalkyl, and C₃₋₈heterocycloalkyl, wherein the heterocycloalkyl groups are optionallysubstituted with 1-4 R^(2c) groups; alternatively, two R² groups linkedto the same carbon are combined to form an oxo group (═O);alternatively, two R² groups are combined to form a heterocycloalkylring having from 5 to 6 ring members and from 1 to 3 heteroatoms eachindependently selected from the group consisting of N, O and S, whereinthe heterocycloalkyl ring is optionally substituted with from 1 to 3R^(2d) groups; R^(2a) and R^(2b) are each independently selected fromthe group consisting of hydrogen and C₁₋₆ alkyl; each R^(2c) isindependently selected from the group consisting of hydrogen, halogen,hydroxy, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, CN, and NR^(2a)R^(2b); eachR^(2d) is independently selected from the group consisting of hydrogenand C₁₋₆ alkyl, or two R^(2d) groups attached to the same ring atom arecombined to form (═O); R³ is selected from the group consisting ofphenyl and pyridyl, each optionally substituted with 1-4 R^(3a) groups;each R^(3a) is independently selected from the group consisting ofhydrogen, halogen, and C₁₋₆ haloalkyl; and subscript n is an integerfrom 0 to 3; or salts and isomers thereof. Such compounds, includingrelacorilant, are disclosed, for example, in U.S. Pat. No. 8,559,784,the entire contents of which is hereby incorporated by reference in itsentirety. Uses and discussion regarding such compounds are furtherdisclosed, for example, in U.S. Pat. Nos. 9,273,047; 9,943,505;9,707,223; 9,956,216; 10,117,852; and 10,151,763, the entire contents ofwhich patents are each hereby incorporated by reference in theirentireties.

In preferred embodiments, the GRM is the nonsteroidal heteroaryl-ketonefused azadecalin GRM compound having the chemical name(R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,termed “relacorilant”, having the formula

In embodiments, the GRM is the nonsteroidal heteroaryl-ketone fusedazadecalin GRM compound is the compound having the chemical name(R)-(1-(4-flurophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,termed “CORT122928”, having the formula

In embodiments, the GRM is the nonsteroidal heteroaryl-ketone fusedazadecalin GRM compound having the chemical name(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,termed “CORT113176”, having the formula

In some cases, the GRM (e.g., a SGRM) is a nonsteroidal compoundcomprising an octahydro fused azadecalin structure. Exemplary GRMscomprising an octahydro fused azadecalin structure include thosedescribed in U.S. Pat. No. 10,047,082 and can be prepared as describedtherein, the disclosure of which U.S. Patent is incorporated herein inits entirety. Such exemplary GRMs may be SGRMs. In some cases, theoctahydro fused azadecalin compound has the formula:

wherein

R¹ is a heteroaryl ring having from 5 to 6 ring members and from 1 to 4heteroatoms each independently selected from the group consisting of N,O and S, optionally substituted with 1-4 groups each independentlyselected from R^(1a);

each R^(1a) is independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, N-oxide, and C₃₋₈ cycloalkyl;

ring J is selected from the group consisting of an aryl ring and aheteroaryl ring having from 5 to 6 ring members and from 1 to 4heteroatoms each independently selected from the group consisting of N,O and S;

each R² is independently selected from the group consisting of hydrogen,C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆alkyl-C₁₋₆ alkoxy, —CN, —OH, —NR^(2a)R^(2b), —C(O)R^(2a), —C(O)OR^(2a),—C(O)NR^(2a)R^(2b), —SR^(2a), —S(O)R^(2a), —S(O)₂ R^(2a), C₃₋₈cycloalkyl, and C₃₋₈ heterocycloalkyl having from 1 to 3 heteroatomseach independently selected from the group consisting of N, O and S;

alternatively, two R² groups on adjacent ring atoms are combined to forma heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3heteroatoms each independently selected from the group consisting of N,O and S, wherein the heterocycloalkyl ring is optionally substitutedwith from 1 to 3 R^(2c) groups;

R^(2a), R^(2b) and R^(2c) are each independently selected from the groupconsisting of hydrogen and C₁₋₆ alkyl;

each R^(3a) is independently halogen; and

subscript n is an integer from 0 to 3;

or salts and isomers thereof.

In embodiments, the octahydro fused azadecalin compound has the formula:

wherein R¹ is selected from the group consisting of pyridine andthiazole, optionally substituted with 1-4 groups each independentlyselected from R^(1a); each R^(1a) is independently selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl,C₁₋₆alkoxy, C₁₋₆ haloalkoxy, N-oxide, and C₃₋₈ cycloalkyl; ring J isselected from the group consisting of phenyl, pyridine, pyrazole, andtriazole; each R² is independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, and —CN; R^(3a) is F;subscript n is an integer from 0 to 3; or salts and isomers thereof.

In embodiments, the GRM is the nonsteroidal octahydro fused azadecalinGRM compound having the chemical name((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,termed “CORT125281”, having the formula

In embodiments, the GRM is the nonsteroidal octahydro fused azadecalinGRM compound having the chemical name((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,termed “CORT125329”, having the formula:

Definitions

As used herein, the term “subject” or “patient” refers to a human ornon-human organism. Thus, the methods and compositions described hereinare applicable to both human and veterinary disease. In certainembodiments, subjects are “patients,” i.e., living humans that arereceiving medical care for a disease or condition. This includes personswith no defined illness who are being investigated for signs ofpathology. Preferred are subjects who have an existing diagnosis of aCushing's syndrome, an example of a disease which may be treated by thecompositions and methods of the present invention.

A disease, disorder, abnormality, adverse event, or condition causingdiscomfort, distress, or disease may be termed a “morbidity”. Amorbidity associated with a disease or disorder, such as, e.g.,hypercortisolemia, Cushing's syndrome, Cushing's disease, etc., may betermed a “comorbidity”.

Acronyms used herein include:

-   ACTH adrenocorticotropic hormone-   proACTH pro-protein of ACTH-   POMC pro-opiomelanocortin-   aPTT activated partial thromboplastin time-   ALT alanine aminotransferase (or “serum glutamic-pyruvie    transaminase” (SGPT))-   AST aspartate aminotransferase (or “serum glutamic-oxaloacetic    transaminase” (SGOT))-   AUC area under the concentration-time curve-   AUC_(0-24h) area under the concentration-time curve over 24 hours-   AUC_(glucose) area under the concentration-time curve for glucose-   AUC_(insulin) area under the concentration-time curve for glucose-   BDI Beck Depression Inventory is a 21-question self-report inventory    that measures depression. BDI-II Total Score is the total score of    Beck Depression Inventory II Cushing QOL Score Cushing Quality of    Life Score. A patient questionnaire that evaluates the    health-related quality of life in patients with Cushing's syndrome-   ECG electrocardiogram-   HOMA-IR Homeostatic model assessment (HOMA) insulin resistance (IR)-   IR insulin resistance-   HbA1c glycated hemoglobin-   IGT impaired glucose tolerance (may be diagnosed with oGTT)-   mITT modified intention to treat-   mPP modified protocol population-   NTx N-telopeptides of type 1 collagen-   oGTT oral glucose tolerance test-   PR interval time between onset of P wave and the R (peak of the QRS    complex)-   QRS Duration time between onset of Q wave and return to baseline of    the S wave-   QT Interval time between onset of the QRS complex and time the T    wave returns to baseline-   QTcB Interval corrected QT interval (Bazett's correction)-   RR Interval time between two R waves (peaks of the QRS complex)-   UFC urinary free cortisol-   Urinary NTx Urinary N-telopeptides cross-links

As used herein, the term “Adrenocorticotrophic Hormone” (ACTH) refers tothe peptide hormone produced by the anterior pituitary gland thatstimulates the adrenal cortex to secrete glucocorticoid hormones, whichhelp cells synthesize glucose, catabolize proteins, mobilize free fattyacids and inhibit inflammation in allergic responses. One suchglucocorticoid hormone is cortisol, which regulates metabolism ofcarbohydrate, fat, and protein metabolism.

As used herein, the term “effective amount” or “therapeutic amount”refers to an amount of a pharmacological agent effective to treat,eliminate, or mitigate at least one symptom of the disease beingtreated. In some cases, “therapeutically effective amount” or “effectiveamount” can refer to an amount of a functional agent or of apharmaceutical composition useful for exhibiting a detectabletherapeutic or inhibitory effect. The effect can be detected by anyassay method known in the art. The effective amount can be an amounteffective to reduce symptoms of cortisol excess, or of hyperglycemia, orof high blood pressure, or of liver fat or fibrosis, or of depression,or bring about other desired beneficial clinical outcomes related topatient improvement.

As used herein, the terms “administer,” “administering,” “administered”or “administration” refer to providing a compound or a composition(e.g., one described herein), to a subject or patient.

As used herein, the term “fasting” refers to a subject or patient whohas not eaten for at least one hour, or at least two hours, or at leastthree hours, or at least four hours, or more. In preferred embodiments,a fasting subject or patient has not eaten for at least four hours. Whena pharmaceutical composition is administered to a fasting subject orpatient, the pharmaceutical composition is administered without food,and the subject or patient does not eat for at least an hour after drugadministration.

As used herein, the terms “hypercortisolemia” and “hypercortisolism” areinterchangeable and refer to excess cortisol. A patient suffering fromhypercortisolemia has Cushing's syndrome, and may suffer from symptomsand other disorders caused by, or related to, such cortisol excess.

As used herein, the term “Cushing's syndrome” refers to disorders causedby excessive activity of the stress hormone cortisol. EndogenousCushing's syndrome is an orphan disease that most often affects adultsaged 20-50. In many cases the disease is caused by a pituitary tumor, oran adrenal tumor. Symptoms vary, but most people experience one or moreof the following manifestations: high blood sugar, metabolic syndrome,pre-diabetes, or diabetes, high blood pressure, upper-body obesity,rounded face, increased fat around the neck, thinning arms and legs,severe fatigue and weak muscles. Irritability, anxiety, cognitivedisturbances and depression are also common. Cushing's syndrome canaffect every organ system in the body and can be lethal if not treatedeffectively.

As used herein, the term “metabolic syndrome” refers to a syndromecharacterized by high blood glucose, high blood pressure, excess bodyfat (particularly around the waist), high levels of blood lipids, andother factors. Metabolic syndrome may indicate increased risk ofcardiovascular disease, diabetes, liver diseases, and other diseases.

As used herein, the term “pre-diabetes” refers to a condition in which asubject may have one or more of elevated blood glucose, abnormal glucosetolerance test results, and other symptoms such as, e.g., elevated bloodpressure, excess weight, excess blood lipids, where such excesses orabnormalities may be slight.

As used herein, the term “diabetes” refers to the disorder of bloodglucose typified by high blood glucose levels, impaired insulinresponse, presence or high levels of ketones in the urine, and othersymptoms as known in the clinical arts. Patients often experiencethirst, frequent urination, fatigue, irritability, and other symptoms.

As used herein, the term “immunotherapy” refers to disease treatments,typically cancer treatments, that affect the immune system of thepatient (e.g., by activating or suppressing its action). Someimmunotherapies include administration of “checkpoint inhibitors” whichenhance the action of immune system T cells to attack cancer cells. Someimmunotherapies include use of the patients T cells which have beenexposed to cancer cells or cancer markers, to enhance the treatment ofcancer in the patent.

As used herein, the term “checkpoint inhibitor” refers to a drug, whichmay be, e.g., a small molecule drug or may be an antibody, whichinhibits the action of proteins or other aspects of immune system cellswhich reduce or block the ability of T cells to attack cancer cells. Thetargets of checkpoint inhibitors may be found in or on T cells, or maybe found in or on cancer cells. Targets of checkpoint inhibitors includethe proteins PD-1, PDL-1, CTLA-4, B7-1, B7-2 and others. Checkpointinhibitors include antibodies to PD-1, PDL-1, CTLA-4, B7-1, B7-2 andothers. For example, the antibody drugs Pembrolizumab (Keytruda),Nivolumab (Opdivo), and Cemiplimab (Libtayo) inhibit PD-1, and theantibody drugs Atezolizumab (Tecentriq), Avelumab (Bavencio), andDurvalumab (Imfinzi) inhibit PDL-1.

As used herein, the term “combination therapy” refers to theadministration of at least two pharmaceutical agents to a subject totreat a disease. The two agents may be administered simultaneously, orsequentially in any order during the entire or portions of the treatmentperiod. The at least two agents may be administered following the sameor different dosing regimens. In some cases, one agent is administeredfollowing a scheduled regimen while the other agent is administeredintermittently. In some cases, both agents are administeredintermittently. In some embodiments, the one pharmaceutical agent, e.g.,a SGRM, is administered daily, and the other pharmaceutical agent, e.g.,a pharmaceutical agent, is administered every two, three, or four days.

As used herein, the term “compound” is used to denote a molecular moietyof unique, identifiable chemical structure. A molecular moiety(“compound”) may exist in a free species form, in which it is notassociated with other molecules. A compound may also exist as part of alarger aggregate, in which it is associated with other molecule(s), butnevertheless retains its chemical identity. A solvate, in which themolecular moiety of defined chemical structure (“compound”) isassociated with a molecule(s) of a solvent, is an example of such anassociated form. A hydrate is a solvate in which the associated solventis water. The recitation of a “compound” refers to the molecular moietyitself (of the recited structure), regardless of whether it exists in afree form or an associated form.

As used herein, the term “pharmaceutically acceptable carrier” isintended to include any and all solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents, and the like, compatible with pharmaceutical administration. Theuse of such media and agents for pharmaceutically active substances iswell known in the art. Except insofar as any conventional media or agentis incompatible with the active compound, use thereof in thecompositions is contemplated. Supplementary active compounds can also beincorporated into the compositions.

The terms “glucocorticoid” (“GC”) or “glucocorticosteroid” equally referto a steroid hormone that binds to a glucocorticoid receptor. GCs aretypically characterized by having 21 carbon atoms, an α,β-unsaturatedketone in ring A, and an α-ketol group attached to ring D. They differin the extent of oxygenation or hydroxylation at C-11, C-17, and C-19;see Rawn, “Biosynthesis and Transport of Membrane Lipids and Formationof Cholesterol Derivatives,” in Biochemistry, Daisy et al. (eds.), 1989,pg. 567.

A mineralocorticoid receptor (MR), also known as a type I glucocorticoidreceptor (GR I), is activated by aldosterone in humans.

As used herein, the term “Glucocorticoid receptor” (“GR”) refers to afamily of intracellular receptors which specifically bind to cortisoland/or cortisol analogs. The glucocorticoid receptor is also referred toas the cortisol receptor. The term includes isoforms of GR, recombinantGR and mutated GR. “Glucocorticoid receptor” (“GR”) refers to the typeII GR which specifically binds to cortisol and/or cortisol analogs suchas dexamethasone (See, e.g., Turner & Muller, J. Mol. Endocrinol. Oct.1, 2005 35 283-292).

“Glucocorticoid receptor modulator” (GRM) refers to any compound whichmodulates any biological response associated with the binding of GR toan agonist. For example, a GR agonist, such as dexamethasone, increasesthe activity of tyrosine aminotransferase (TAT) in HepG2 cells (a humanliver hepatocellular carcinoma cell line; ECACC, UK). Accordingly, GRmodulators of the present invention can be identified by measuring theability of the compound to modulate the effect of dexamethasone. TATactivity can be measured as outlined in the literature by A. Ali et al.,J. Med. Chem., 2004, 47, 2441-2452. A modulator is a compound with anEC₅₀ (half maximal effective concentration) of less than 10 micromolar.See Example 1, infra.

As used herein, the term “selective glucocorticoid receptor modulator”(SGRM) refers to any composition or compound which modulates anybiological response associated with the binding of a GR to an agonist.By “selective,” the drug preferentially binds to the GR rather thanother nuclear receptors, such as the progesterone receptor (PR), themineralocorticoid receptor (MR) or the androgen receptor (AR). It ispreferred that the selective glucocorticoid receptor modulator bind GRwith an affinity that is 10× greater (1/10^(th) the K_(d) value) thanits affinity to the MR, AR, or PR, both the MR and PR, both the MR andAR, both the AR and PR, or to the MR, AR, and PR. In a more preferredembodiment, the selective glucocorticoid receptor modulator binds GRwith an affinity that is 100× greater (1/100^(th) the K_(d) value) thanits affinity to the MR, AR, or PR, both the MR and PR, both the MR andAR, both the AR and PR, or to the MR, AR, and PR. In another embodiment,the selective glucocorticoid receptor modulator binds GR with anaffinity that is 1000× greater (1/1000^(th) the K_(d) value) than itsaffinity to the MR, AR, or PR, both the MR and PR, both the MR and AR,both the AR and PR, or to the MR, AR, and PR.

As used herein, the terms “selective glucocorticoid receptor modulator”and “SGRM” do not include ORG 34517, or 11-(substituted phenyl)-estra-4,9-diene derivatives, or 11-(substituted phenyl)-estra-4, 9-dienederivatives of the following formula:

wherein A is a residue of a 5- or 6-membered ring containing 2heteroatoms which are not connected to each other and independentlyselected from O and S, the ring being optionally substituted with one ormore halogen atoms, or A is a residue of a 5- or 6-membered ring whereinno double C——C bonds are present, containing 1 heteroatom selected fromO and S, which heteroatom is connected to the phenyl group at theposition indicated with an asterisk, the ring being optionallysubstituted with one or more halogen atoms; R1 is H or I-oxo(1-4C)alkyl;R2 is H, (1-8C)alkyl, halogen or CF3; X is selected from (H, OH), O, andNOH; and the interrupted line represents an optional bond (see, e.g.,claim 1 of U.S. Pat. No. 8,658,128).

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients such as the said compounds,their tautomeric forms, their derivatives, their analogues, theirstereoisomers, their polymorphs, their deuterated species, theirpharmaceutically acceptable salts, esters, ethers, metabolites, mixturesof isomers, their pharmaceutically acceptable solvates andpharmaceutically acceptable compositions in specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to a pharmaceutical composition is intended to encompass aproduct comprising the active ingredient (s), and the inert ingredient(s) that make up the carrier, as well as any product which results,directly or indirectly, in combination, complexation or aggregation ofany two or more of the ingredients, or from dissociation of one or moreof the ingredients, or from other types of reactions or interactions ofone or more of the ingredients. Accordingly, the pharmaceuticalcompositions of the present invention are meant to encompass anycomposition made by admixing compounds of the present invention andtheir pharmaceutically acceptable carriers.

In some embodiments, the term “consisting essentially of” refers to acomposition in a formulation whose only active ingredient is theindicated active ingredient, however, other compounds may be includedwhich are for stabilizing, preserving, etc. the formulation, but are notinvolved directly in the therapeutic effect of the indicated activeingredient. In some embodiments, the term “consisting essentially of”can refer to compositions which contain the active ingredient andcomponents which facilitate the release of the active ingredient. Forexample, the composition can contain one or more components that provideextended release of the active ingredient over time to the subject. Insome embodiments, the term “consisting” refers to a composition, whichcontains the active ingredient and a pharmaceutically acceptable carrieror excipient.

“Pharmaceutically-acceptable excipient” and “pharmaceutically-acceptablecarrier” refer to a substance that aids the administration of an activeagent to—and absorption by—a subject and can be included in thecompositions of the present invention without causing a significantadverse toxicological effect on the patient. Non-limiting examples ofpharmaceutically-acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors and colors, and the like. One of ordinary skill in the art willrecognize that other pharmaceutical excipients are useful in the presentinvention.

As used herein, the phrase “nonsteroidal backbone” in the context ofSGRMs refers to SGRMs that do not share structural homology to, or arenot modifications of, cortisol with its steroid backbone containingseventeen carbon atoms, bonded in four fused rings. Such compoundsinclude synthetic mimetics and analogs of proteins, including partiallypeptidic, pseudopeptidic and non-peptidic molecular entities.

Nonsteroidal SGRM compounds include SGRMs comprising a fused azadecalinstructure (which may also be termed a fused azadecalin backbone), SGRMscomprising a heteroaryl ketone fused azadecalin structure (which mayalso be termed a heteroaryl ketone fused azadecalin backbone), and SGRMscomprising an octahydro fused azadecalin structure (which may also betermed an octahydro fused azadecalin backbone). Exemplary nonsteroidalglucocorticoid receptor modulators comprising a fused azadecalinstructure include those described in U.S. Pat. Nos. 7,928,237 and8,461,172. Exemplary nonsteroidal glucocorticoid receptor modulatorscomprising a heteroaryl ketone fused azadecalin structure include thosedescribed in U.S. Pat. No. 8,859,774 and continuations thereof.Exemplary nonsteroidal glucocorticoid receptor modulators comprising anoctahydro fused azadecalin structure include those described in U.S.Pat. No. 10,047,082. The entire contents of all patents and patentapplications cited herein are hereby incorporated by reference in theirentireties.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

“Alkyl” refers to a straight or branched, saturated, aliphatic radicalhaving the number of carbon atoms indicated. Alkyl can include anynumber of carbons, such as C₁₋₂, C₁₋₃, C₁₋₄, C₁₋₅, C₁₋₆, C₁₋₇, C₁₋₈,C₁₋₉, C₁₋₁₀, C₂₋₃, C₂₋₄, C₂₋₅, C₂₋₆, C₃₋₄, C₃₋₅, C₃₋₆, C₄₋₅, C₄₋₆, andC₅₋₆. For example, C₁₋₆ alkyl includes, but is not limited to, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, and hexyl.

“Alkoxy” refers to an alkyl group having an oxygen atom that connectsthe alkyl group to the point of attachment: alkyl-O—. As for the alkylgroup, alkoxy groups can have any suitable number of carbon atoms, suchas C₁₋₆. Alkoxy groups include, for example, methoxy, ethoxy, propoxy,iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,pentoxy, hexoxy, etc.

“Halogen” refers to fluorine, chlorine, bromine, and iodine.

“Haloalkyl” refers to alkyl, as defined above, where some or all of thehydrogen atoms are replaced with halogen atoms. As for the alkyl group,haloalkyl groups can have any suitable number of carbon atoms, such asC₁₋₆, and include trifluoromethyl, fluoromethyl, etc.

The term “perfluoro” can be used to define a compound or radical whereall the hydrogens are replaced with fluorine. For example,perfluoromethane includes 1,1,1-trifluoromethyl.

“Haloalkoxy” refers to an alkoxy group where some or all of the hydrogenatoms are substituted with halogen atoms. As for the alkyl group,haloalkoxy groups can have any suitable number of carbon atoms, such asC₁₋₆. The alkoxy groups can be substituted with 1, 2, 3, or morehalogens. When all the hydrogens are replaced with a halogen, forexample by fluorine, the compounds are per-substituted, for example,perfluorinated. Haloalkoxy includes, but is not limited to,trifluoromethoxy, 2,2,2,-trifluoroethoxy, and perfluoroethoxy.

“Cycloalkyl” refers to a saturated or partially unsaturated, monocyclic,fused bicyclic, or bridged polycyclic ring assembly containing from 3 to12 ring atoms, or the number of atoms indicated. Cycloalkyl can includeany number of carbons, such as C₃₋₆, C₄₋₆, C₅₋₆, C₃₋₈, C₄₋₈, C₅₋₈, C₆₋₈,C₃₋₉, C₃₋₁₀, C₃₋₁₁, and C₃₋₁₂. Saturated monocyclic cycloalkyl ringsinclude, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl ringsinclude, for example, norbornane, [2.2.2] bicyclooctane,decahydronaphthalene, and adamantane. Cycloalkyl groups can also bepartially unsaturated, having one or more double or triple bonds in thering. Representative cycloalkyl groups that are partially unsaturatedinclude, but are not limited to, cyclobutene, cyclopentene, cyclohexene,cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene,cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene,and norbornadiene. When cycloalkyl is a saturated monocyclic C₃₋₈cycloalkyl, exemplary groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. When cycloalkyl is a saturated monocyclic C₃₋₆ cycloalkyl,exemplary groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

“Heterocycloalkyl” refers to a saturated ring system having from 3 to 12ring members and from 1 to 4 heteroatoms of N, O, and S. Additionalheteroatoms can also be useful, including but not limited to, B, Al, Si,and P. The heteroatoms can also be oxidized, such as, but not limitedto, —S(O)— and —S(O)₂—. Heterocycloalkyl groups can include any numberof ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitablenumber of heteroatoms can be included in the heterocycloalkyl groups,such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3to 4. The heterocycloalkyl group can include groups such as aziridine,azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine,pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers),oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane,thiirane, thietane, thiolane (tetrahydrothiophene), thiane(tetrahydrothiopyran), oxazolidine, isoxalidine, thiazolidine,isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine,dioxane, or dithiane. The heterocycloalkyl groups can also be fused toaromatic or non-aromatic ring systems to form members including, but notlimited to, indoline.

When heterocycloalkyl includes 3 to 8 ring members and 1 to 3heteroatoms, representative members include, but are not limited to,pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene,thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine,isoxazolidine, thiazolidine, isothiazolidine, morpholine,thiomorpholine, dioxane and dithiane. Heterocycloalkyl can also form aring having 5 to 6 ring members and 1 to 2 heteroatoms, withrepresentative members including, but not limited to, pyrrolidine,piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine,imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine,isothiazolidine, and morpholine.

“Aryl” refers to an aromatic ring system having any suitable number ofring atoms and any suitable number of rings. Aryl groups can include anysuitable number of ring atoms, such as 6, 7, 8, 9, 10, 11, 12, 13, 14,15, or 16 ring atoms, as well as from 6 to 10, 6 to 12, or 6 to 14 ringmembers. Aryl groups can be monocyclic, fused to form bicyclic ortricyclic groups, or linked by a bond to form a biaryl group.Representative aryl groups include phenyl, naphthyl and biphenyl. Otheraryl groups include benzyl, that has a methylene linking group. Somearyl groups have from 6 to 12 ring members, such as phenyl, naphthyl, orbiphenyl. Other aryl groups have from 6 to 10 ring members, such asphenyl or naphthyl. Some other aryl groups have 6 ring members, such asphenyl. Aryl groups can be substituted or unsubstituted.

“Heteroaryl” refers to a monocyclic, fused bicyclic, or tricyclicaromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5of the ring atoms are a heteroatom such as N, O, or S. Additionalheteroatoms can also be useful, including but not limited to, B, Al, Si,and P. The heteroatoms can also be oxidized, such as, but not limitedto, N-oxide, —S(O)—, and —S(O)₂—. Heteroaryl groups can include anynumber of ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Anysuitable number of heteroatoms can be included in the heteroaryl groups,such as 1, 2, 3, 4, or 5; or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups can have from 5 to 8ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring membersand from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms.The heteroaryl group can include groups such as pyrrole, pyridine,imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine,pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene,furan, thiazole, isothiazole, oxazole, and isoxazole. The heteroarylgroups can also be fused to aromatic ring systems, such as a phenylring, to form members including, but not limited to, benzopyrroles suchas indole and isoindole, benzopyridines such as quinoline andisoquinoline, benzopyrazine (quinoxaline), benzopyrimidine(quinazoline), benzopyridazines such as phthalazine and cinnoline,benzothiophene, and benzofuran. Other heteroaryl groups includeheteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groupscan be substituted or unsubstituted.

The heteroaryl groups can be linked via any position on the ring. Forexample, pyrrole includes 1-, 2-, and 3-pyrrole; pyridine includes 2-,3- and 4-pyridine; imidazole includes 1-, 2-, 4- and 5-imidazole;pyrazole includes 1-, 3-, 4- and 5-pyrazole; triazole includes 1-, 4-and 5-triazole; tetrazole includes 1- and 5-tetrazole; pyrimidineincludes 2-, 4-, 5- and 6-pyrimidine; pyridazine includes 3- and4-pyridazine; 1,2,3-triazine includes 4- and 5-triazine; 1,2,4-triazineincludes 3-, 5- and 6-triazine; 1,3,5-triazine includes 2-triazine;thiophene includes 2- and 3-thiophene; furan includes 2- and 3-furan;thiazole includes 2-, 4- and 5-thiazole; isothiazole includes 3-, 4- and5-isothiazole; oxazole includes 2-, 4- and 5-oxazole; isoxazole includes3-, 4- and 5-isoxazole; indole includes 1-, 2- and 3-indole; isoindoleincludes 1- and 2-isoindole; quinoline includes 2-, 3- and 4-quinoline;isoquinoline includes 1-, 3- and 4-isoquinoline; quinazoline includes 2-and 4-quinoazoline; cinnoline includes 3- and 4-cinnoline;benzothiophene includes 2- and 3-benzothiophene; and benzofuran includes2- and 3-benzofuran.

Some heteroaryl groups include those having from 5 to 10 ring membersand from 1 to 3 ring atoms including N, O, or S, such as pyrrole,pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine,pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene,furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole,quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine,cinnoline, benzothiophene, and benzofuran. Other heteroaryl groupsinclude those having from 5 to 8 ring members and from 1 to 3heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole,pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, andisoxazole. Some other heteroaryl groups include those having from 9 to12 ring members and from 1 to 3 heteroatoms, such as indole, isoindole,quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine,cinnoline, benzothiophene, benzofuran and bipyridine. Still otherheteroaryl groups include those having from 5 to 6 ring members and from1 to 2 ring heteroatoms including N, O or S, such as pyrrole, pyridine,imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan,thiazole, isothiazole, oxazole, and isoxazole.

Some heteroaryl groups include from 5 to 10 ring members and onlynitrogen heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole,triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and1,3,5-isomers), indole, isoindole, quinoline, isoquinoline, quinoxaline,quinazoline, phthalazine, and cinnoline. Other heteroaryl groups includefrom 5 to 10 ring members and only oxygen heteroatoms, such as furan andbenzofuran. Some other heteroaryl groups include from 5 to 10 ringmembers and only sulfur heteroatoms, such as thiophene andbenzothiophene. Still other heteroaryl groups include from 5 to 10 ringmembers and at least two heteroatoms, such as imidazole, pyrazole,triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and1,3,5-isomers), thiazole, isothiazole, oxazole, isoxazole, quinoxaline,quinazoline, phthalazine, and cinnoline.

“Heteroatoms” refers to O, S, or N.

“Salt” refers to acid or base salts of the compounds used in the methodsof the present invention. Illustrative examples ofpharmaceutically-acceptable salts are mineral acid (hydrochloric acid,hydrobromic acid, phosphoric acid, and the like) salts, organic acid(acetic acid, propionic acid, glutamic acid, citric acid, and the like)salts, and quaternary ammonium (methyl iodide, ethyl iodide, and thelike) salts. It is understood that the pharmaceutically-acceptable saltsare non-toxic. Additional information on suitablepharmaceutically-acceptable salts can be found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, which is incorporated herein by reference.

“Isomers” refers to compounds with the same chemical formula but whichare structurally distinguishable.

“Tautomer” refers to one of two or more structural isomers which existin equilibrium and which are readily converted from one form to another.

Descriptions of compounds of the present invention are limited byprinciples of chemical bonding known to those skilled in the art.Accordingly, where a group may be substituted by one or more of a numberof substituents, such substitutions are selected so as to comply withprinciples of chemical bonding and to produce compounds which are notinherently unstable—and/or would be known to one of ordinary skill inthe art as likely to be unstable under ambient conditions—such asaqueous, neutral, or physiological conditions.

The methods disclosed herein are applicable for treating patientssuffering from Cushing's syndrome, Cushing's Disease, and otherdisorders caused by, or characterized by, or including as a symptom,cortisol excess (hypercortisolemia); hyperglycemia secondary tohypercortisolemia; metabolic syndrome, pre-diabetes, or diabetes; aliver disease (e.g., fatty liver disease, non-alcoholic fatty liverdisease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liverdiseases, liver fibrosis, and other liver disorders); a cardiac disorder(including, e.g., prolonged Q-T interval or other disorder of the heartrhythm, with or without Left Ventricular Hypertrophy (LVH)); high bloodpressure; cancer; a psychological disorder (e.g., depression, such aspsychotic major depression); weight gain (including weight gain due toantipsychotic medication), and other diseases and disorders.

Generally, treatment of cortisol excess (hypercortisolemia) can beprovided by administering an effective amount of a pharmaceutical agentin combination with an effective amount of a glucocorticoid receptormodulator (GRM) of any chemical structure or mechanism of action. Inembodiments, the GRM is a selective GRM (SGRM). In embodiments,treatment of cortisol excess can be provided by administering aneffective amount of a pharmaceutical agent in combination with aneffective amount of a SGRM. In preferred embodiments, treatment ofcortisol excess can be provided by administering an effective amount ofa pharmaceutical agent in combination with an effective amount of anonsteroidal SGRM. Provided herein are classes of exemplary GRMs, and inparticular, exemplary nonsteroidal SGRMs, and specific members of suchclasses. However, one of skill in the art will readily recognize otherrelated or unrelated GRMs and SGRMs that can be employed in thetreatment methods described herein.

Exemplary GRMs comprising a heteroaryl ketone fused azadecalin structureinclude those described in U.S. Pat. No. 8,859,774, which can beprepared as disclosed therein, and is incorporated herein in itsentirety. Such exemplary GRMs may be SGRMs. In some cases, the GRMcomprising a heteroaryl ketone fused azadecalin structure has thefollowing structure:

wherein

R¹ is a heteroaryl ring having from 5 to 6 ring members and from 1 to 4heteroatoms each independently selected from the group consisting of N,O and S, optionally substituted with 1-4 groups each independentlyselected from R^(1a);

each R^(1a) is independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, —CN, N-oxide, C₃₋₈ cycloalkyl, and C₃₋₈ heterocycloalkyl;

ring J is selected from the group consisting of a cycloalkyl ring, aheterocycloalkyl ring, an aryl ring and a heteroaryl ring, wherein theheterocycloalkyl and heteroaryl rings have from 5 to 6 ring members andfrom 1 to 4 heteroatoms each independently selected from the groupconsisting of N, O and S;

each R² is independently selected from the group consisting of hydrogen,C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆alkyl-C₁₋₆ alkoxy, —CN, —OH, —NR^(2a)R^(2b), —C(O)R^(2a), —C(O)OR^(2a),—C(O)NR^(2a)R^(2b), —SR^(2a), —S(O)R^(2a), —S(O)₂ R^(2a), C₃₋₈cycloalkyl, and C₃₋₈ heterocycloalkyl, wherein the heterocycloalkylgroups are optionally substituted with 1-4 R^(2c) groups;

alternatively, two R² groups linked to the same carbon are combined toform an oxo group (═O);

alternatively, two R² groups are combined to form a heterocycloalkylring having from 5 to 6 ring members and from 1 to 3 heteroatoms eachindependently selected from the group consisting of N, O and S, whereinthe heterocycloalkyl ring is optionally substituted with from 1 to 3R^(2d) groups;

R^(2a) and R^(2b) are each independently selected from the groupconsisting of hydrogen and C₁₋₆ alkyl;

each R^(2c) is independently selected from the group consisting ofhydrogen, halogen, hydroxy, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —CN, and—NR^(2a)R^(2b);

each R^(2d) is independently selected from the group consisting ofhydrogen and C₁₋₆ alkyl, or two R^(2d) groups attached to the same ringatom are combined to form (═O);

R³ is selected from the group consisting of phenyl and pyridyl, eachoptionally substituted with 1-4 R^(3a) groups;

each R^(3a) is independently selected from the group consisting ofhydrogen, halogen, and C₁₋₆ haloalkyl; and

subscript n is an integer from 0 to 3;

or salts and isomers thereof.

In preferred embodiments, the GRM is the nonsteroidal heteroaryl-ketonefused azadecalin GRM compound having the chemical name(R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,termed “relacorilant”, having the formula

Exemplary GRMs comprising an octahydro fused azadecalin structureinclude those described in U.S. Pat. No. 10,047,082 and can be preparedas described therein, the disclosure of which U.S. Patent isincorporated herein in its entirety. Such exemplary GRMs may be SGRMs.In some cases, the GRM comprising an octahydro fused azadecalinstructure has the following structure:

wherein

R¹ is a heteroaryl ring having from 5 to 6 ring members and from 1 to 4heteroatoms each independently selected from the group consisting of N,O and S, optionally substituted with 1-4 groups each independentlyselected from R^(1a);

each R^(1a) is independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, N-oxide, and C₃₋₈ cycloalkyl;

ring J is selected from the group consisting of an aryl ring and aheteroaryl ring having from 5 to 6 ring members and from 1 to 4heteroatoms each independently selected from the group consisting of N,O and S;

each R² is independently selected from the group consisting of hydrogen,C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆alkyl-C₁₋₆ alkoxy, —CN, —OH, —NR^(2a)R^(2b), —C(O)R^(2a), —C(O)OR^(2a),—C(O)NR^(2a)R^(2b), —SR^(2a), —S(O)R^(2a), —S(O)₂ R^(2a), C₃₋₈cycloalkyl, and C₃₋₈ heterocycloalkyl having from 1 to 3 heteroatomseach independently selected from the group consisting of N, O and S;

alternatively, two R² groups on adjacent ring atoms are combined to forma heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3heteroatoms each independently selected from the group consisting of N,O and S, wherein the heterocycloalkyl ring is optionally substitutedwith from 1 to 3 R^(2c) groups;

R^(2a), R^(2b) and R^(2c) are each independently selected from the groupconsisting of hydrogen and C₁₋₆ alkyl;

each R^(3a) is independently halogen; and

subscript n is an integer from 0 to 3;

or salts and isomers thereof.

In embodiments, the octahydro fused azadecalin compound has the formula:

wherein R¹ is selected from the group consisting of pyridine andthiazole, optionally substituted with 1-4 groups each independentlyselected from R^(1a); each R^(1a) is independently selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, N-oxide, and C₃₋₈ cycloalkyl; ring J isselected from the group consisting of phenyl, pyridine, pyrazole, andtriazole; each R² is independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, and —CN; R^(3a) is F;subscript n is an integer from 0 to 3; or salts and isomers thereof.

Exemplary glucocorticoid receptor antagonists comprising an octohydrofused azadecalin structure include those described in U.S. Pat. No.10,047,082. In embodiments, the octahydro fused azadecalin compound isthe compound((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone(“CORT125281”) which has the structure:

In embodiments, the GRM is the nonsteroidal octahydro fused azadecalinGRM compound having the chemical name((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,termed “CORT125329”, having the formula:

To determine whether a test compound is a SGRM, the compound is firstsubjected to assays to measure its ability to bind to the GR and inhibitGR-mediated activities, which determines whether the compound is aglucocorticoid receptor modulator. The compound, if confirmed to be aglucocorticoid receptor modulator, is then subjected to a selectivitytest to determine whether the compound can bind specifically to GR ascompared to non-GR proteins, such as the estrogen receptor, theprogesterone receptor, the androgen receptor, or the mineralocorticoidreceptor. In one embodiment, a SGRM binds to GR at a substantiallyhigher affinity, e.g., at least 10 times higher affinity, than to non-GRproteins. A SGRM may exhibit a 100-fold, 1000-fold or greaterselectivity for binding to GR relative to binding to non GR proteins.

A test compound's ability to bind to the glucocorticoid receptor can bemeasured using a variety of assays, for example, by screening for theability of the test compound to compete with a glucocorticoid receptorligand, such as dexamethasone, for binding to the glucocorticoidreceptor. Those of skill in the art will recognize that there are anumber of ways to perform such competitive binding assays. In someembodiments, the glucocorticoid receptor is pre-incubated with a labeledglucocorticoid receptor ligand and then contacted with a test compound.This type of competitive binding assay may also be referred to herein asa binding displacement assay. A decrease of the quantity of labeledligand bound to glucocorticoid receptor indicates that the test compoundbinds to the glucocorticoid receptor. In some cases, the labeled ligandis a fluorescently labeled compound (e.g., a fluorescently labeledsteroid or steroid analog). Alternatively, the binding of a testcompound to the glucocorticoid receptor can be measured directly with alabeled test compound. This latter type of assay is called a directbinding assay.

Both direct binding assays and competitive binding assays can be used ina variety of different formats. The formats may be similar to those usedin immunoassays and receptor binding assays. For a description ofdifferent formats for binding assays, including competitive bindingassays and direct binding assays, see Basic and Clinical Immunology 7thEdition (D. Stites and A. Terr ed.) 1991; Enzyme Immunoassay, E. T.Maggio, ed., CRC Press, Boca Raton, Fla. (1980); and “Practice andTheory of Enzyme Immunoassays,” P. Tijssen, Laboratory Techniques inBiochemistry and Molecular Biology, Elsevier Science Publishers B.V.Amsterdam (1985), each of which is incorporated herein by reference.

In solid phase competitive binding assays, for example, the samplecompound can compete with a labeled analyte for specific binding siteson a binding agent bound to a solid surface. In this type of format, thelabeled analyte can be a glucocorticoid receptor ligand and the bindingagent can be glucocorticoid receptor bound to a solid phase.Alternatively, the labeled analyte can be labeled glucocorticoidreceptor and the binding agent can be a solid phase glucocorticoidreceptor ligand. The concentration of labeled analyte bound to thecapture agent is inversely proportional to the ability of a testcompound to compete in the binding assay.

Alternatively, the competitive binding assay may be conducted in theliquid phase, and any of a variety of techniques known in the art may beused to separate the bound labeled protein from the unbound labeledprotein. For example, several procedures have been developed fordistinguishing between bound ligand and excess bound ligand or betweenbound test compound and the excess unbound test compound. These includeidentification of the bound complex by sedimentation in sucrosegradients, gel electrophoresis, or gel isoelectric focusing;precipitation of the receptor-ligand complex with protamine sulfate oradsorption on hydroxylapatite; and the removal of unbound compounds orligands by adsorption on dextran-coated charcoal (DCC) or binding toimmobilized antibody. Following separation, the amount of bound ligandor test compound is determined.

Alternatively, a homogenous binding assay may be performed in which aseparation step is not needed. For example, a label on theglucocorticoid receptor may be altered by the binding of theglucocorticoid receptor to its ligand or test compound. This alterationin the labeled glucocorticoid receptor results in a decrease or increasein the signal emitted by label, so that measurement of the label at theend of the binding assay allows for detection or quantitation of theglucocorticoid receptor in the bound state. A wide variety of labels maybe used. The component may be labeled by any one of several methods.Useful radioactive labels include those incorporating ³H, ¹²⁵I, ³⁵S,¹⁴C, or ³²P. Useful non-radioactive labels include those incorporatingfluorophores, chemiluminescent agents, phosphorescent agents,electrochemiluminescent agents, and the like. Fluorescent agents areespecially useful in analytical techniques that are used to detectshifts in protein structure such as fluorescence anisotropy and/orfluorescence polarization. The choice of label depends on sensitivityrequired, ease of conjugation with the compound, stability requirements,and available instrumentation. For a review of various labeling orsignal producing systems which may be used, see U.S. Pat. No. 4,391,904,which is incorporated herein by reference in its entirety for allpurposes. The label may be coupled directly or indirectly to the desiredcomponent of the assay according to methods well known in the art. Insome cases, a test compound is contacted with a GR in the presence of afluorescently labeled ligand (e.g., a steroid or steroid analog) with aknown affinity for the GR, and the quantity of bound and free labeledligand is estimated by measuring the fluorescence polarization of thelabeled ligand.

ii. Activity

1) HepG2 Tyrosine Aminotransferase (TAT) Assay

Compounds that have demonstrated the desired binding affinity to GR aretested for their activity in inhibiting GR mediated activities. Thecompounds are typically subject to a Tyrosine Aminotransferase Assay(TAT assay), which assesses the ability of a test compound to inhibitthe induction of tyrosine aminotransferase activity by dexamethasone.See Example 1. GR modulators that are suitable for the method disclosedherein have an IC₅₀ (half maximal inhibition concentration) of less than10 micromolar. Other assays, including but not limited to thosedescribed below, can also be deployed to confirm the GR modulationactivity of the compounds.

2) Cell-Based Assays

Cell-based assays which involve whole cells or cell fractions containingglucocorticoid receptors can also be used to assay for a test compound'sbinding or modulation of activity of the glucocorticoid receptor.Exemplary cell types that can be used according to the methods of theinvention include, e.g., any mammalian cells including leukocytes suchas neutrophils, monocytes, macrophages, eosinophils, basophils, mastcells, and lymphocytes, such as T cells and B cells, leukemia cells,Burkitt's lymphoma cells, tumor cells (including mouse mammary tumorvirus cells), endothelial cells, fibroblasts, cardiac cells, musclecells, breast tumor cells, ovarian cancer carcinomas, cervicalcarcinomas, glioblastomas, liver cells, kidney cells, and neuronalcells, as well as fungal cells, including yeast. Cells can be primarycells or tumor cells or other types of immortal cell lines. Of course,the glucocorticoid receptor can be expressed in cells that do notexpress an endogenous version of the glucocorticoid receptor.

In some cases, fragments of the glucocorticoid receptor, as well asprotein fusions, can be used for screening. When molecules that competefor binding with the glucocorticoid receptor ligands are desired, the GRfragments used are fragments capable of binding the ligands (e.g.,dexamethasone). Alternatively, any fragment of GR can be used as atarget to identify molecules that bind the glucocorticoid receptor.Glucocorticoid receptor fragments can include any fragment of, e.g., atleast 20, 30, 40, 50 amino acids up to a protein containing all but oneamino acid of glucocorticoid receptor.

In some embodiments, a reduction in signaling triggered byglucocorticoid receptor activation is used to identify glucocorticoidreceptor modulators. Signaling activity of the glucocorticoid receptorcan be determined in many ways. For example, downstream molecular eventscan be monitored to determine signaling activity. Downstream eventsinclude those activities or manifestations that occur as a result ofstimulation of a glucocorticoid receptor . Exemplary downstream eventsuseful in the functional evaluation of transcriptional activation andantagonism in unaltered cells include upregulation of a number ofglucocorticoid response element (GRE)-dependent genes (PEPCK, tyrosineamino transferase, aromatase). In addition, specific cell typessusceptible to GR activation may be used, such as osteocalcin expressionin osteoblasts which is downregulated by glucocorticoids; primaryhepatocytes which exhibit glucocorticoid mediated upregulation of PEPCKand glucose-6-phosphate (G-6-Pase)). GRE-mediated gene expression hasalso been demonstrated in transfected cell lines using well-knownGRE-regulated sequences (e.g., the mouse mammary tumor virus promoter(MMTV) transfected upstream of a reporter gene construct). Examples ofuseful reporter gene constructs include luciferase (luc), alkalinephosphatase (ALP) and chloramphenicol acetyl transferase (CAT). Thefunctional evaluation of transcriptional repression can be carried outin cell lines such as monocytes or human skin fibroblasts. Usefulfunctional assays include those that measure IL-1beta stimulated IL-6expression; the downregulation of collagenase, cyclooxygenase-2 andvarious chemokines (MCP-1, RANTES); LPS stimulated cytokine release,e.g., TNFα; or expression of genes regulated by NFkB or AP-1transcription factors in transfected cell-lines.

Compounds that are tested in whole-cell assays can also be tested in acytotoxicity assay. Cytotoxicity assays are used to determine the extentto which a perceived effect is due to non-glucocorticoid receptorbinding cellular effects. In an exemplary embodiment, the cytotoxicityassay includes contacting a constitutively active cell with the testcompound. Any decrease in cellular activity indicates a cytotoxiceffect.

Further illustrative of the many assays which can be used to identifycompositions utilized in the methods of the invention, are assays basedon glucocorticoid activities in vivo. For example, assays that assessthe ability of a putative GR modulator to inhibit uptake of 3H-thymidineinto DNA in cells which are stimulated by glucocorticoids can be used.Alternatively, the putative GR modulator can complete with3H-dexamethasone for binding to a hepatoma tissue culture GR (see, e.g.,Choi, et al., Steroids 57:313-318, 1992). As another example, theability of a putative GR modulator to block nuclear binding of3H-dexamethasone-GR complex can be used (Alexandrova et al., J. SteroidBiochem. Mol. Biol. 41:723-725, 1992). To further identify putative GRmodulators, kinetic assays able to discriminate between glucocorticoidagonists and modulators by means of receptor-binding kinetics can alsobe used (as described in Jones, Biochem J. 204:721-729, 1982).

In another illustrative example, the assay described by Daune, Molec.Pharm. 13:948-955, 1977; and in U.S. Pat. No. 4,386,085, can be used toidentify anti-glucocorticoid activity. Briefly, the thymocytes ofadrenalectomized rats are incubated in nutritive medium containingdexamethasone with the test compound (the putative GR modulator) atvarying concentrations. ³H-uridine is added to the cell culture, whichis further incubated, and the extent of incorporation of radiolabel intopolynucleotide is measured. Glucocorticoid agonists decrease the amountof ³H-uridine incorporated. Thus, a GR modulator will oppose thiseffect.

The GR modulators selected above are then subject to a selectivity assayto determine whether they are SGRMs. Typically, selectivity assaysinclude testing a compound that binds glucocorticoid receptor in vitrofor the degree of binding to non-glucocorticoid receptor proteins.Selectivity assays may be performed in vitro or in cell based systems,as described above. Binding may be tested against any appropriate nonglucocorticoid receptor protein, including antibodies, receptors,enzymes, and the like. In an exemplary embodiment, thenon-glucocorticoid receptor binding protein is a cell-surface receptoror nuclear receptor. In another exemplary embodiment, thenon-glucocorticoid receptor protein is a steroid receptor, such asestrogen receptor, progesterone receptor, androgen receptor, ormineralocorticoid receptor.

The selectivity of the antagonist for the GR relative to the MR can bemeasured using a variety of assays known to those of skill in the art.For example, specific antagonists can be identified by measuring theability of the antagonist to bind to the GR compared to the MR (see,e.g., U.S. Pat. Nos. 5,606,021; 5,696,127; 5,215,916; 5,071,773). Suchan analysis can be performed using either a direct binding assay or byassessing competitive binding to the purified GR or MR in the presenceof a known ligand. In an exemplary assay, cells that stably express theglucocorticoid receptor or mineralocorticoid receptor (see, e.g., U.S.Pat. No. 5,606,021) at high levels are used as a source of purifiedreceptor. The affinity of the ligandfor the receptor is then directlymeasured. Those GR modulators that exhibit at least a 10 fold, 100-foldhigher affinity, often 1000-fold, for the GR relative to the MR are thenselected for use in the methods of the invention.

The selectivity assay may also include assaying the ability to inhibitGR-mediated activities, but not MR-mediated activities. One method ofidentifying such a GR-specific modulator is to assess the ability of anantagonist to prevent activation of reporter constructs usingtransfection assays (see, e.g., Bocquel et al, J. Steroid Biochem Molec.Biol. 45:205-215, 1993; U.S. Pat. Nos. 5,606,021, 5,929,058). In anexemplary transfection assay, an expression plasmid encoding thereceptor and a reporter plasmid containing a reporter gene linked toreceptor-specific regulatory elements are cotransfected into suitablereceptor-negative host cells. The transfected host cells are thencultured in the presence and absence of a hormone, such as cortisol oran analog thereof, able to activate the hormone responsivepromoter/enhancer element of the reporter plasmid. Next the transfectedand cultured host cells are monitored for induction (i.e., the presence)of the product of the reporter gene sequence. Finally, the expressionand/or steroid binding-capacity of the hormone receptor protein (codedfor by the receptor DNA sequence on the expression plasmid and producedin the transfected and cultured host cells), is measured by determiningthe activity of the reporter gene in the presence and absence of anantagonist. The antagonist activity of a compound may be determined incomparison to known antagonists of the GR and MR receptors (see, e.g.,U.S. Pat. No. 5,696,127). Efficacy is then reported as the percentmaximal response observed for each compound relative to a referenceantagonist compound. GR modulators that exhibits at least a 100-fold,often 1000-fold or greater, activity towards the GR relative to the MR,PR, or AR are then selected for use in the methods disclosed herein.

An exemplar nonsteroidal SGRM that can be used in the methods disclosedherein is relacorilant, i.e.,(R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,which has the following structure:

Pharmaceutical Compositions and Administration

In embodiments, the present invention provides a pharmaceuticalcomposition for treating cortisol excess, the pharmaceutical compositionincluding a pharmaceutically acceptable excipient and a GRM. In someembodiments, the pharmaceutical composition includes a pharmaceuticallyacceptable excipient and a SGRM. In preferred embodiments, thepharmaceutical composition includes a pharmaceutically acceptableexcipient and a nonsterodial SGRM.

GRMs and SGRMs (as used herein, GRMs and SGRMs include nonsteroidal GRMsand nonsteroidal SGRMS), can be prepared and administered in a widevariety of oral, parenteral and topical dosage forms. Oral preparationsinclude tablets, pills, powder, dragees, capsules, liquids, lozenges,gels, syrups, slurries, suspensions, etc., suitable for ingestion by thepatient. GRMs and SGRMs can also be administered by injection, that is,intravenously, intramuscularly, intracutaneously, subcutaneously,intraduodenally, or intraperitoneally. Also, GRMs and SGRMs can beadministered by inhalation, for example, intranasally. Additionally,GRMs and SGRMs can be administered transdermally. Accordingly, thepresent invention also provides pharmaceutical compositions including apharmaceutically acceptable carrier or excipient and a GRM or SGRM.

For preparing pharmaceutical compositions from GRMs and SGRMs,pharmaceutically acceptable carriers can be either solid or liquid.Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. A solid carrier can beone or more substances, which may also act as diluents, flavoringagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material. Details on techniques for formulation andadministration are well described in the scientific and patentliterature, see, e.g., the latest edition of Remington's PharmaceuticalSciences, Maack Publishing Co, Easton Pa. (“Remington's”).

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component, a GRM or SGRM. In tablets, theactive component is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

The powders and tablets preferably contain from 5% or 10% to 70% of theactive compound. Suitable carriers are magnesium carbonate, magnesiumstearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, a lowmelting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as a carrier providing a capsule in which theactive component with or without other carriers, is surrounded by acarrier, which is thus in association with it. Similarly, cachets andlozenges are included. Tablets, powders, capsules, pills, cachets, andlozenges can be used as solid dosage forms suitable for oraladministration.

Suitable solid excipients are carbohydrate or protein fillers include,but are not limited to sugars, including lactose, sucrose, mannitol, orsorbitol; starch from corn, wheat, rice, potato, or other plants;cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, orsodium carboxymethylcellulose; and gums including arabic and tragacanth;as well as proteins such as gelatin and collagen. If desired,disintegrating or solubilizing agents may be added, such as thecross-linked polyvinyl pyrrolidone, agar, alginic acid, or a saltthereof, such as sodium alginate.

Dragee cores are provided with suitable coatings such as concentratedsugar solutions, which may also contain gum arabic, talc,polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titaniumdioxide, lacquer solutions, and suitable organic solvents or solventmixtures. Dyestuffs or pigments may be added to the tablets or drageecoatings for product identification or to characterize the quantity ofactive compound (i.e., dosage). Pharmaceutical preparations of theinvention can also be used orally using, for example, push-fit capsulesmade of gelatin, as well as soft, sealed capsules made of gelatin and acoating such as glycerol or sorbitol. Push-fit capsules can contain GRmodulator mixed with a filler or binders such as lactose or starches,lubricants such as talc or magnesium stearate, and, optionally,stabilizers. In soft capsules, the GR modulator compounds may bedissolved or suspended in suitable liquids, such as fatty oils, liquidparaffin, or liquid polyethylene glycol with or without stabilizers.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizers, and thickening agents as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gumtragacanth and gum acacia, and dispersing or wetting agents such as anaturally occurring phosphatide (e.g., lecithin), a condensation productof an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate),a condensation product of ethylene oxide with a long chain aliphaticalcohol (e.g., heptadecaethylene oxycetanol), a condensation product ofethylene oxide with a partial ester derived from a fatty acid and ahexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensationproduct of ethylene oxide with a partial ester derived from fatty acidand a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate).The aqueous suspension can also contain one or more preservatives suchas ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, oneor more flavoring agents and one or more sweetening agents, such assucrose, aspartame or saccharin. Formulations can be adjusted forosmolarity.

Also included are solid form preparations, which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

Oil suspensions can be formulated by suspending a SGRM in a vegetableoil, such as arachis oil, olive oil, sesame oil or coconut oil, or in amineral oil such as liquid paraffin; or a mixture of these. The oilsuspensions can contain a thickening agent, such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents can be added to provide apalatable oral preparation, such as glycerol, sorbitol or sucrose. Theseformulations can be preserved by the addition of an antioxidant such asascorbic acid. As an example of an injectable oil vehicle, see Minto, J.Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical formulationsof the invention can also be in the form of oil-in-water emulsions. Theoily phase can be a vegetable oil or a mineral oil, described above, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth,naturally occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan mono-oleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. Theemulsion can also contain sweetening agents and flavoring agents, as inthe formulation of syrups and elixirs. Such formulations can alsocontain a demulcent, a preservative, or a coloring agent.

GRMs and SGRMs can be delivered by transdermally, by a topical route,formulated as applicator sticks, solutions, suspensions, emulsions,gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

GRMs and SGRMs can also be delivered as microspheres for slow release inthe body. For example, microspheres can be administered via intradermalinjection of drug -containing microspheres, which slowly releasesubcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995; asbiodegradable and injectable gel formulations (see, e.g., Gao Pharm.Res. 12:857-863, 1995); or, as microspheres for oral administration(see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). Bothtransdermal and intradermal routes afford constant delivery for weeks ormonths.

The pharmaceutical formulations of the invention can be provided as asalt and can be formed with many acids, including but not limited tohydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc.Salts tend to be more soluble in aqueous or other protonic solvents thatare the corresponding free base forms. In other cases, the preparationmay be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2% sucrose,2%-7% mannitol at a pH range of 4.5 to 5.5, that is combined with bufferprior to use.

In another embodiment, the formulations of the invention can bedelivered by the use of liposomes which fuse with the cellular membraneor are endocytosed, i.e., by employing ligands attached to the liposome,or attached directly to the oligonucleotide, that bind to surfacemembrane protein receptors of the cell resulting in endocytosis. Byusing liposomes, particularly where the liposome surface carries ligandsspecific for target cells, or are otherwise preferentially directed to aspecific organ, one can focus the delivery of the GR modulator into thetarget cells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul.13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro,Am. J. Hosp. Pharm. 46:1576-1587, 1989).

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component, a GRM or SGRM. The unitdosage form can be a packaged preparation, the package containingdiscrete quantities of preparation, such as packeted tablets, capsules,and powders in vials or ampoules. Also, the unit dosage form can be acapsule, tablet, cachet, or lozenge itself, or it can be the appropriatenumber of any of these in packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to6000 mg, most typically 50 mg to 500 mg. Suitable dosages also includeabout 1 mg, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400,500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700,1800, 1900, or 2000 mg, according to the particular application and thepotency of the active component. The composition can, if desired, alsocontain other compatible therapeutic agents.

In some cases, the effective amount of the GRM (e.g., a relacorilant) isa daily dose of between 1 and 100 mg/kg/day. In some embodiments, thedaily dose of the GRM is 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 30, 40,50 60, 70, 80, 90 or 100 mg/kg/day. In some cases, the GRM isadministrated for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75,or 80 weeks.

Single or multiple administrations of formulations can be administereddepending on the dosage and frequency as required and tolerated by thepatient. The formulations should provide a sufficient quantity of activeagent to effectively treat the disease state. Thus, in one embodiment,the pharmaceutical formulation for oral administration of a GRM is in adaily amount of between about 0.01 to about 150 mg per kilogram of bodyweight per day (mg/kg/day). In some embodiments, the daily amount isfrom about 1.0 to 100 mg/kg/day, 5 to 50 mg/kg/day, 10 to 30 mg/kg/day,and 10 to 20 mg/kg/day. Lower dosages can be used, particularly when thedrug is administered to an anatomically secluded site, such as thecerebral spinal fluid (CSF) space, in contrast to administration orally,into the blood stream, into a body cavity or into a lumen of an organ.Substantially higher dosages can be used in topical administration.Actual methods for preparing parenterally administrable formulationswill be known or apparent to those skilled in the art and are describedin more detail in such publications as Remington's, supra. See alsoNieman, In “Receptor Mediated Antisteroid Action,” Agarwal, et al.,eds., De Gruyter, New York (1987).

The duration of treatment with a GRM or SGRM to reduce the cortisolexcess can vary according to the severity of the condition in a subjectand the subject's response to GRMs or SGRMs. In some embodiments, GRMsand SGRMs can be administered for a period of about 1 week to 104 weeks(2 years), more typically about 6 weeks to 80 weeks, most typicallyabout 9 to 60 weeks. Suitable periods of administration also include 5to 9 weeks, 5 to 16 weeks, 9 to 16 weeks, 16 to 24 weeks, 16 to 32weeks, 24 to 32 weeks, 24 to 48 weeks, 32 to 48 weeks, 32 to 52 weeks,48 to 52 weeks, 48 to 64 weeks, 52 to 64 weeks, 52 to 72 weeks, 64 to 72weeks, 64 to 80 weeks, 72 to 80 weeks, 72 to 88 weeks, 80 to 88 weeks,80 to 96 weeks, 88 to 96 weeks, and 96 to 104 weeks. Suitable periods ofadministration also include 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 24, 25, 30, 32, 35, 40, 45, 48 50, 52, 55, 60, 64, 65,68, 70, 72, 75, 80, 85, 88 90, 95, 96, 100, and 104 weeks. Generallyadministration of a GRM or SGRM should be continued until clinicallysignificant reduction or amelioration is observed. Treatment with theGRM or SGRM in accordance with the invention may last for as long as twoyears or even longer.

In some embodiments, administration of a GRM or SGRM is not continuousand can be stopped for one or more periods of time, followed by one ormore periods of time where administration resumes. Suitable periodswhere administration stops include 5 to 9 weeks, 5 to 16 weeks, 9 to 16weeks, 16 to 24 weeks, 16 to 32 weeks, 24 to 32 weeks, 24 to 48 weeks,32 to 48 weeks, 32 to 52 weeks, 48 to 52 weeks, 48 to 64 weeks, 52 to 64weeks, 52 to 72 weeks, 64 to 72 weeks, 64 to 80 weeks, 72 to 80 weeks,72 to 88 weeks, 80 to 88 weeks, 80 to 96 weeks, 88 to 96 weeks, and 96to 100 weeks. Suitable periods where administration stops also include5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 25, 30,32, 35, 40, 45, 48 50, 52, 55, 60, 64, 65, 68, 70, 72, 75, 80, 85, 8890, 95, 96, and 100 weeks.

The dosage regimen also takes into consideration pharmacokineticsparameters well known in the art, i.e., the rate of absorption,bioavailability, metabolism, clearance, and the like (see, e.g.,Hidalgo-Aragones (1996) J Steroid Biochem. Mol. Biol. 58:611-617;Groning (1996) Pharmazie 51:337-341; Fotherby (1996) Contraception54:59-69; Johnson (1995) J. Pharm. Sci. 84:1144-1146; Rohatagi (1995)Pharmazie 50:610-613; Brophy (1983) Eur. J. Clin. Pharmacol. 24:103-108;the latest Remington's, supra). The state of the art allows theclinician to determine the dosage regimen for each individual patient,GR modulator and disease or condition treated.

SGRMs can be used in combination with other active agents known to beuseful in modulating a glucocorticoid receptor, or with adjunctiveagents that may not be effective alone, but may contribute to theefficacy of the active agent.

In some embodiments, co-administration includes administering one activeagent, a GRM or SGRM, within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24hours of a second active agent. Co-administration includes administeringtwo active agents simultaneously, approximately simultaneously (e.g.,within about 1, 5, 10, 15, 20, or 30 minutes of each other), orsequentially in any order. In some embodiments, co-administration can beaccomplished by co-formulation, i.e., preparing a single pharmaceuticalcomposition including both active agents. In other embodiments, theactive agents can be formulated separately. In another embodiment, theactive and/or adjunctive agents may be linked or conjugated to oneanother.

After a pharmaceutical composition including a GR modulator of theinvention has been formulated in an acceptable carrier, it can be placedin an appropriate container and labeled for treatment of an indicatedcondition. For administration of a GRM or SGRM, such labeling wouldinclude, e.g., instructions concerning the amount, frequency and methodof administration.

The pharmaceutical compositions of the present invention can be providedas a salt and can be formed with many acids, including but not limitedto hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic,etc. Salts tend to be more soluble in aqueous or other protonic solventsthat are the corresponding free base forms. In other cases, thepreparation may be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2%sucrose, 2%-7% mannitol at a pH range of 4.5 to 5.5, that is combinedwith buffer prior to use.

In another embodiment, the compositions of the present invention areuseful for parenteral administration, such as intravenous (IV)administration or administration into a body cavity or lumen of anorgan. The formulations for administration will commonly comprise asolution of the compositions of the present invention dissolved in apharmaceutically acceptable carrier. Among the acceptable vehicles andsolvents that can be employed are water and Ringer's solution, anisotonic sodium chloride. In addition, sterile fixed oils canconventionally be employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid can likewisebe used in the preparation of injectables. These solutions are sterileand generally free of undesirable matter. These formulations may besterilized by conventional, well known sterilization techniques. Theformulations may contain pharmaceutically acceptable auxiliarysubstances as required to approximate physiological conditions such aspH adjusting and buffering agents, toxicity adjusting agents, e.g.,sodium acetate, sodium chloride, potassium chloride, calcium chloride,sodium lactate and the like. The concentration of the compositions ofthe present invention in these formulations can vary widely, and will beselected primarily based on fluid volumes, viscosities, body weight, andthe like, in accordance with the particular mode of administrationselected and the patient's needs. For IV administration, the formulationcan be a sterile injectable preparation, such as a sterile injectableaqueous or oleaginous suspension. This suspension can be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents. The sterile injectable preparation canalso be a sterile injectable solution or suspension in a nontoxicparenterally-acceptable diluent or solvent, such as a solution of1,3-butanediol.

I. Combination Therapies

Various combinations with a GRM or SGRM and another pharmaceutical agent(which may be a small molecule drug, an large molecule such as anantibody or peptide, or may be an immunotherapy agent, or a cancerchemotherapy agent, or a combination of such agents and compounds) maybe employed to treat a patient. By “combination therapy” or “incombination with”, it is not intended to imply that the therapeuticagents must be administered at the same time and/or formulated fordelivery together, although these methods of delivery are within thescope described herein. The GRM or SGRM and the pharmaceutical agent canbe administered following the same or different dosing regimen. In someembodiments, the GRM or SGRM and the pharmaceutical agent isadministered sequentially in any order during the entire or portions ofthe treatment period. In some embodiments, the GRM or SGRM and the othertherapeutic agent is administered simultaneously or approximatelysimultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes ofeach other). Non-limiting examples of combination therapies are asfollows, with administration of the GRM or SGRM and other therapeuticagent for example, GRM or SGRM is “A” and other therapeutic agent orcompound, given as part of therapeutic regime, is “B”:

A/B/AB/A/BB/B/AA/A/BA/B/BB/A/AA/B/B/B B/A/B/B B/B/B/A  B/B/A/BA/A/B/B  A/B/A/B  A/B/B/A B/B/A/A B/A/B/A  B/A/A/B A/A/A/B  B/A/A/A A/B/A/A A/A/B/A

Administration of the therapeutic compounds or agents to a patient willfollow general protocols for the administration of such compounds,taking into account the toxicity, if any, of the therapy. Surgicalintervention may also be applied in combination with the descirbedtherapy.

The present methods can be combined with other means of treatment suchas surgery, radiation, targeted therapy, immunotherapy, use of growthfactor inhibitors, or anti-angiogenesis factors.

All patents, patent publications, publications, and patent applicationscited in this specification are hereby incorporated by reference hereinin their entireties as if each individual publication or patentapplication were specifically and individually indicated to beincorporated by reference.

EXAMPLES

The following examples are provided by way of illustration only and notby way of limitation. Those of skill will readily recognize a variety ofnoncritical parameters which could be changed or modified to yieldessentially similar results.

Example 1 HEPG2 Tyrosine Aminotransferase (TAT) Assay

The following protocol describes an assay for measuring induction of TATby dexamethasone in HepG2 cells (a human liver hepatocellular carcinomacell line; ECACC, UK). HepG2 cells are cultured using MEME mediasupplemented with 10% (v/v) foetal bovine serum; 2 mM L-glutamine and 1%(v/v) NEAA at 37° C., 5%/95% (v/v) CO2/air. The HepG2 cells are then becounted and adjusted to yield a density of 0.125×10⁶ cells/ml in RPMI1640 without phenol red, 10% (v/v) charcoal stripped FBS, 2 mML-glutamine and seeded at 25,000 cells/well in 200 μl into 96 well,sterile, tissue culture micro titre plates, and incubated at 37° C., 5%CO₂ for 24 hours.

Growth media are then removed and replaced with assay media {RPMI 1640without phenol red, 2 mM L-glutamine+10 μM forskolin}. Test compoundsare then screened against a challenge of 100 nM dexamethasone. Compoundsare then be serially half log diluted in 100% (v/v) dimethylsupfoxidefrom a 10 mM stock. Then an 8-point half-log dilution curve aregenerated followed by a 1:100 dilution into assay media to give a 10×final assay of the compound concentration, this results in final assayof the compound concentration that ranged 10 to 0.003 μM in 0.1% (v/v)dimethylsulfoxide.

Test compounds are pre-incubated with cells in micro-titre plates for 30minutes at 37° C., 5/95 (v/v) CO₂/air, before the addition of 100 nMdexamethasone and then subsequently for 20 hours to allow optimal TATinduction.

HepG2 cells are then lysed with 30 μl of cell lysis buffer containing aprotease inhibitor cocktail for 15 minutes at 4° C. 155 μl of substratemixture can then be added containing 5.4 mM Tyrosine sodium salt, 10.8mM alpha ketoglutarate and 0.06 mM pyridoxal 5′ phosphate in 0.1Mpotassium phosphate buffer (pH 7.4). After 2 hours incubation at 37° C.the reaction can be terminated by the addition of 15 μl of 10M aqueouspotassium hydroxide solution, and the plates incubated for a further 30minutes at 37° C. The TAT activity product can be measured by absorbanceat λ 340 nm.

IC₅₀ values can be calculated by plotting % inhibition (normalised to100 nM dexamethasone TAT stimulation) v. compound concentration andfitting the data to a 4 parameter logistic equation. IC₅₀ values canconverted to Ki (equilibrium dissociation constant) using the Cheng andPrusoff equation, assuming the antagonists were competitive inhibitorswith respect to dexamethasone.

Example 2 Clinical Responses to Relacorilant

Responses to Relacorilant in Healthy Subjects

Studies of relacorilant in human volunteers have shown that daily dosingresults in achievement of steady state levels by Day 7. Single doses offrom 5 mg to 500 mg of relacorilant are well-tolerated in humansubjects, as are 14 days of relacorilant dosing at doses of 50 mg, 150mg, and 250 mg as well. Some subjects reported mild to moderatemusculoskeletal AEs with repeat doses up to 250 mg. A transientreduction in platelet count was observed in some subjects in anon-dose-dependent manner; this resolved by study end. In addition, somesubjects received 500-mg relacorilant. Some subjects reported(non-serious) musculoskeletal adverse events.

Example 3 Clinical Responses to Relacorilant

Responses to Relacorilant in Cushing's Syndrome Patients

Relacorilant was administered to (or self-administered by) male andfemale fasting Cushing's syndrome patients (n=35) (in multiple capsuleseach containing 50 milligrams (mg) of relacorilant) orally once per day(in the morning with no food for 4 hours before and 1 hour afterdosing). The patients had a confirmed diagnosis of endogenous Cushing'ssyndrome and at least one of the following: a) Type 2 diabetes orimpaired glucose tolerance, and b) uncontrolled or untreatedhypertension. All patients gave informed consent before participating inany study-related procedures.

The patients received daily doses of relacorilant at their initial dosefor four weeks, after which the daily dose was increased in 50 mgincrements, as tolerable, every four weeks. The first 17 patients toenroll (Group 1, the “low-dose cohort”, LD) received 100 mg relacorilantper day for 4 weeks, then 150 mg relacorilant per day for 4 weeks, then200 mg relacorilant per day for 4 weeks (12 weeks total). The next 18patients (Group 2, the “high dose cohort”, HD) started at 250 mgrelacorilant per day; this was increased to 300 mg relacorilant per dayafter four weeks, and then to 350 mg relacorilant per day following fourweeks at 300 mg per day, and finally, where tolerated, after four weeksat 350 mg per day, the daily dose was increased to 400 mg relacorilantper day for a final four weeks (16 weeks total).

The study protocol called for patient visits to the study site atscreening, on Day 1 (baseline), Weeks 2, 4, 6, 8, 10, and 12, and aftera 4-week follow-up period for Group 1. For Group 2, the protocol calledfor patient visits to the study site at screening, on Day 1 (baseline),Weeks 2, 4, 6, 8, 10, 12, 14, and 16, and after a 4-week follow-upperiod. Patient dosing will be done at home, except on days of studyvisits.

Patient monitoring during the study included monitoring of blood levelsof relacorilant and its metabolites measured predose and at 1, 2, 4, 6,and 8 hours postdose at Weeks 2, 6, and 10, and predose only at Weeks 4,8, and 12/early termination (ET) (for patients in Group 1). For patientsin Group 2, blood levels of relacorilant and its metabolites weremeasured predose and at 1, 2, 4, 6, and 8 hours postdose at Weeks 2, 6,10, and 14 and predose only at Weeks 4, 8, 12, and 16/early termination(ET). The safety protocol also included assessments by physicalexamination findings, vital signs, ECG results, pregnancy tests,clinical laboratory test results (hematology and chemistry panels),adverse events (AEs), and concomitant medications. Safety andpharmacokinetic (PK) data were reviewed to confirm the appropriatenessof the administered dose levels, including following escalation tohigher doses (i.e., 2 weeks following dose escalation to 200 mg/day),and when steady-state PK data were available for 6 patients who reachedtheir highest relacorilant dose (e.g., Week 10 for 350 mg relacorilantdaily doses and Week 14 for 400 mg relacorilant daily doses) and at theend of the study.

Response criteria for hyperglycemia were changes from baseline inglucose tolerance as measured by: ≥0.5% decrease in HbA1c, normalizationor ≥50 mg/dL decrease in 2-hr OGTT glucose, or decrease in total dailyinsulin (≥25%) or sulfonylurea dose (≥50%). Response criteria forhypertension (HTN) was a ≥5 mm Hg decrease in mean systolic and/ordiastolic blood pressure (SBP/DBP).

In this study, regarding the high dose cohort (Group 2), fifty percentof patients with hyperglycemia achieved improved glucose control, asshown by (i) a 0.5 percent or greater reduction in HbA1c or (ii)normalization of 2-hour oGTT glucose or decreased by at least 50 mg/dLor (iii) a 25 percent decrease in antidiabetic medications. Sixty-fourpercent of patients with uncontrolled hypertension achieved a fivemillimeter or greater drop in either systolic or diastolic bloodpressure, as measured by 24-hour ambulatory monitoring. Patients in thehigh-dose group also met a wide range of secondary endpoints, includingstatistically significant improvements in hypercoagulopathy, liverfunction, serum osteocalcin (a marker of bone formation), cognitivefunction, depression and quality of life.

Therapeutic improvements noted in at least some patients includedimprovements in blood clotting measures indicating improvement inhypercoagulopathy and lessening of risk of embolism; improvements inother blood indicators (e.g., platelet count and others); improvement inindicators of heart function and heart rhythm (e.g., improvement inabnormalities of cardiac function, improvement in indicators of leftventricular hypertrophy; improvements in measures of liver function;improvements in measures of immune system function and status;improvements in measures of bone health; improvements in patients'quality of life; improvements in patients' pyschological well-being(e.g., lessening of depression); and improvements in patients' glucoselevels suggesting improvement in, or lessening risk of, metabolicsyndrome, pre-diabetes or diabetes.

These and further results are presented in TABLE 1.

Relacorilant was well-tolerated by these patients. There was no evidenceof relacorilant having any progesterone receptor affinity; and none ofthe patients suffered hypokalemia. There were no drug-related seriousadverse events.

FIG. 1 illustrates the improvement in glucose control resulting fromrelacorilant administration. 50 percent of patients with hyperglycemiain the high-dose cohort achieved improved glucose control (see FIG. 1 ).The response rate in patients with hypertension was 64 percent (see FIG.2 ). These response rates are comparable to those exhibited by patientsat 16 weeks and a dose of 1200 mg in Korlym's pivotal trial (e.g.,Fleseriu et al, J. Clin. Endocrinol. Metab. 97(6):2039-2049 (2012);Fleseriu et al., J Clin Endocrinol Metab, 99(10):3718-3727 (2014).

Clinical results of the study are presented in Table 1. Results arereported for the modified intent to treat population (mITT) and themodified protocol population (modified per protocol: mPP); intention totreat (ITT) analysis includes every subject who is randomized accordingto randomized treatment assignment. It ignores noncompliance, protocoldeviations, withdrawal, and anything that happens after randomization.In contrast, per-protocol (PP) analysis refers to inclusion in theanalysis of only those patients who strictly adhered to the protocol.The PP analysis provides an estimate of the true efficacy of anintervention, i.e., among those who completed the treatment as planned.

TABLE 1 Means and Wilcoxon Signed Rank P-values for Key Outcomes byGroup and Population for Change from Baseline to Last Observed (mITT andmPP) Group 1 Group 2 Overall Category Parameter Population Mean P-ValueMean P-Value Mean P-Value Abnormal Factor IX (%) mITT −40.8 0.0625 −4.20.8125 −22.5 0.0293 at mPP −40.8 0.0625 −4.2 0.8125 −22.5 0.0293Baseline Factor X (%) mITT −15.8 0.0625 −22 0.2500 −18.13 0.0078 mPP−15.8 0.0625 −22 0.2500 −18.13 0.0078 Thrombin-Antithrombin mITT 1.610.6484 −9.83 0.0923 −3.88 0.5469 (mcg/L) mPP 1.61 0.6484 −9.83 0.0923−3.88 0.5469 von Willebrand Factor mITT −18.5 0.3125 −18.5 0.3125 (%)mPP −18.5 0.3125 −18.5 0.3125 All ALT (SGPT) (U/L) mITT −7.88 0.0105−13.35 0.0002 −10.62 <0.0001 Subjects AST (SGOT) (U/L) mITT −2.71 0.1663−7.31 0.0039 −4.94 0.0013 AUCglucose mITT −3.11 0.0171 −0.8 0.4973 −1.960.0214 (hr*mmol/L) mPP −3.63 0.0171 −1.24 0.3394 −2.48 0.0097 AUCinsulinmITT −33.28 0.1465 −32.26 0.7354 −32.77 0.2348 (hr*μU/mL) mPP −38.790.1677 −37.39 0.5693 −38.12 0.2075 Absolute Eosinophils mITT 0.05 0.00730.05 0.2686 0.05 0.0060 (10{circumflex over ( )}{super 9 AbsoluteLymphocytes mITT −0.15 0.4874 0.26 0.0225 0.05 0.3778 (10{circumflexover ( )}{super 9 BDI-II Total Score mITT −3.06 0.2096 −3.94 0.0056−3.48 0.0044 mPP −4.47 0.1479 −3.87 0.0083 −4.19 0.0047 Cushing QOLScore mITT 6.25 0.0186 8.07 0.0636 7.13 0.0024 mPP 6.25 0.0186 7.640.1050 6.9 0.0042 ECG Median Heart Rate Safety 8 0.0505 5.23 0.2078 6.70.0111 (beats/min) mITT 8 0.0505 5.23 0.2078 6.7 0.0111 Factor IX (%)mITT −11.59 0.1475 6.44 0.3964 −2.85 0.5578 mPP −11.59 0.1475 6.440.3964 −2.85 0.5578 Factor VIII (%) mITT −11.94 0.2385 −26.38 0.0492−18.94 0.0219 mPP −11.94 0.2385 −26.38 0.0492 −18.94 0.0219 Factor X (%)mITT −0.06 0.9914 −8.88 0.0033 −4.33 0.0672 mPP −0.06 0.9914 −8.880.0033 −4.33 0.0672 Fructosamine (μmol/L), mITT −6.85 0.2749 −21.580.0010 −13.92 0.0021 IGT mPP −8.08 0.1812 −18.92 0.0098 −13.28 0.0052HOMA-IR, IGT mITT 0.05 0.6355 −3.2 0.0327 −1.58 0.0642 mPP 0.39 0.7354−3.28 0.0923 −1.37 0.1383 POMC and proACTH mITT 7.91 0.0234 7.91 0.0234(pmol/L) mPP 7.91 0.0234 7.91 0.0234 PR Interval, Aggregate Safety 2.720.3778 −4.2 0.1726 −0.4 0.9238 (msec) mITT 2.72 0.3778 −4.2 0.1726 −0.40.9238 Part A - Total Time to mITT −3.65 0.1534 −4.67 0.0079 −4.130.0030 Complete T mPP −3.65 0.1534 −4.67 0.0079 −4.13 0.0030 Part B -Total Time to mITT −15.94 0.0552 −34.6 <0.0001 −24.69 <0.0001 Complete TmPP −15.94 0.0552 −34.6 <0.0001 −24.69 <0.0001 Platelet Count (10⁹/L)mITT −62.82 0.0003 −74.82 0.0002 −68.82 <0.0001 QRS Duration, Safety−0.79 0.4510 −0.77 0.5416 −0.78 0.2884 Aggregate (msec) mITT −0.790.4510 −0.77 0.5416 −0.78 0.2884 QT Interval, Aggregate Safety −15.850.0505 −11.04 0.3028 −13.6 0.0159 (msec) mITT −15.85 0.0505 −11.040.3028 −13.6 0.0159 QTcB Interval, Safety 5.58 0.2247 2.28 0.8040 4.030.2685 Aggregate (msec) mITT 5.58 0.2247 2.28 0.8040 4.03 0.2685 QTcFInterval, Safety −1.98 0.5477 −2.54 0.9780 −2.24 0.6214 Aggregate (msec)mITT −1.98 0.5477 −2.54 0.9780 −2.24 0.6214 RR Interval, AggregateSafety −93.14 0.0202 −56.67 0.2524 −76.04 0.0081 (msec) mITT −93.140.0202 −56.67 0.2524 −76.04 0.0081 Serum Bone Alkaline mITT 1.82 0.0957−1.09 0.1329 0.41 0.7866 Phosphatase ( mPP 1.82 0.0957 −1.09 0.1329 0.410.7866 Serum Osteocalcin mITT 4.57 0.0161 1.33 0.2129 3 0.0097 (μg/L)mPP 4.68 0.0080 1.33 0.2129 3.06 0.0069 Thrombin-Antithrombin mITT 1.480.3843 −7.13 0.2979 −2.69 0.9930 (mcg/L) mPP 1.48 0.3843 −7.13 0.2979−2.69 0.9930 Urinary NTx mITT 2.21 0.3906 0.63 0.7928 1.37 0.4521(nmolBCE/mmol) mPP 2.21 0.3906 0.63 0.7928 1.37 0.4521 aPTT (sec) mITT2.24 0.2820 0.5 0.1191 1.45 0.0456 mPP 2.24 0.2820 0.5 0.1191 1.450.0456 von Willebrand Factor mITT 2.88 0.9632 10.88 0.6413 6.76 0.6812(%) mPP 2.88 0.9632 10.88 0.6413 6.76 0.6812

These results show a statistically significant reduction in theAUC^(glucose) in patients with hyperglycemia. Response rates were 15.4%in the LD group and 50% in the HD group by weeks 12 and 16,respectively. Response rates for hypertension were 41.7% in the LD groupand 63.6% in the HD group by weeks 12 and 16, respectively. In additionto these primary endpoints, significant changes in various secondaryendpoints related to cortisol excess were seen, including improvementsin hypercoagulopathy, liver function, insulin sensitivity, cognitivefunction, depression, and Cushing quality of life (QoL) score. Someweight loss was observed in many of the patients. The most commontreatment-emergent adverse events (TEAEs) were back pain, edema,headache, and nausea. Five serious TEAEs were reported in 4 patients.The serious TEAEs were all from the HD group and were related primarilyto the unmasking of chronic conditions that were suppressed from chroniccortisol excess. No drug-induced hypokalemia or vaginal bleeding wereseen in the study.

These results show that relacorilant is effective in reducing many ofthe effects of excess cortisol in Cushing's syndrome patients. Thus,relacorilant treatment is believed to be useful for treating Cushing'ssyndrome. In addition, relacorilant is believed to be useful fortreating fatty liver diseases (see, e.g., the ALT, AST, HOMA, and othermeasures in Table 1). Furthermore, relacorilant is believed to be usefulfor treating bone disorders (see, e.g., the serum osteocalcin measure inTable 1). Relacorilant is further believed to be useful for treatingheart ailments, including left ventricular hypertrophy, arrhythmias, andother forms of heart disease (see, e.g., the heart measures such as QTin Table 1). In addition, relacorilant is believed to be useful fortreating blood clotting disorders, depression, and for improvingpatients' quality of life. Relacorilant may be useful in combinationwith immunotherapy agents, such as, e.g., checkpoint inhibitors, and maybe useful in diagnostic tests as well.

These results show that relacorilant at dosages up to 400 mg/daydemonstrated clinical improvement in hyperglycemia and hypertension, andalso demonstrated improvement in other endpoints related to cortisolexcess. Relacorilant was generally well tolerated. Thus, relacorilantoffers clinical benefits of potent glucocorticoid modulation withoutundesirable anti-progesterone or mineralocorticoid (due to cortisolincrease) mediated effects.

GR Antagonism is a Clinically Validated Treatment for Cushing Syndrome

In the first study with relacorilant in patients with Cushing syndrome(CORT125134-451; NCT02804750), a total of 35 patients were enrolled at19 centers in the United States, Italy, United Kingdom, Hungary, andNetherlands.

Twenty-eight patients (80%) had an adrenocorticotropin hormone(ACTH)-dependent source of Cushing syndrome (either pituitary orectopic) and 7 patients (20%) had an adrenal source of Cushing syndrome.The efficacy of the drug in Cushing syndrome was assessed based on theimprovement of morbidities associated with excess cortisol activity,e.g. hyperglycaemia, hypertension, cognitive dysfunction, depression,poor quality of life, hypercoagulopathy and obesity. (A morbidityassociated with excess cortisol, e.g., associated withhypercortisolemia, Cushing's syndrome, Cushing's disease, etc., is alsotermed a “comorbidity”.)

Consistent with the expected dose effect, 2/13 (15.4%) patients withhyperglycaemia treated with doses up to 200 mg and half of the patients(6/12) with hyperglycaemia treated with doses up to 400 mg showed robustevidence of glyacemic improvement. Response was based on ≥0.5% reductionof HbA1c associated with reduction or discontinuation of diabetesmedications or clinically significant reduction (≥50 mg/dL decrease) ornormalisation of the 2-hour glucose measurement from an oral glucosetolerance test (OGTT). Among patients with uncontrolled hypertension,5/12 (41.7%) of the patients receiving doses up to 200 mg daily, and7/11 (63.6%) of the patients receiving doses up to 400 mg daily showed aclinically significant improvement (≥5 mmHg reduction) in their 24-hourmean systolic and diastolic BP measured with 24-hour ambulatory bloodpressure monitoring. These patients also showed clinically significantimprovement in their nocturnal and daytime blood pressures. Thisclinical improvement was observed without any episodes of drug inducedhypokalemia—a commonly seen adverse event in patients treated witheither mifepristone or metyrapone. As expected, patients treated withrelacorilant also demonstrated no adverse effects of progesteronereceptor antagonism, an additional benefit over mifepristone.

Besides the improvement in hyperglycaemia and hypertension, generallyobserved within two weeks of achieving a therapeutic dose ofrelacorilant, significant improvements were also observed in a number ofother cortisol-related comorbidities as seen in TABLE 2 below:

TABLE 2 Secondary endpoint improvements in patients with Cushing’ssyndrome Secondary endpoint P-value Cushing QoL Score <0.005  Cognitivetests (Trail Making Test Part A) <0.005  Cognitive tests (Trail MakingTest Part B) <0.0001 Beck Depression Scale <0.003  Coagulopathy (FactorVIII) <0.03  Coagulopathy (Platelets) <0.0001 Coagulopathy (APTT) <0.05 Liver Function Tests (ALT, AST) <0.002  Fructosamine <0.006  Osteocalcin<0.01  Eosinophils <0.007 

Although greater weight loss is generally seen the longer the durationof treatment with GR antagonists, significant weight changes wereobserved within 3 months in half of the patients in the relacorilantstudy with an average weight loss of 2.2 kg in patients treated withdoses up to 200 mg daily and 5.1 kg in patients treated with doses up to400 mg daily.

Improvement/normalization of abnormally elevated coagulation factorscaused by excess cortisol activity was observed as early as after onemonth of treatment with relacorilant. This is in contrast to what isobserved after curative surgery for pituitary Cushing syndrome caseswhere coagulation factors start to decrease 3 months post-surgery andoften remain elevated for at least 6 months post-surgery (Trementino etal., Neuroendocrinology 92 Suppl 1:55-59 (2010). Considering the highrisk of thrombotic events in patients with active Cushing syndrome aswell as following curative surgery, relacorilant might even be an optionfor pre-operative coagulation control of patients at high risk ofperi-and post-operative thrombotic events.

In patients with adrenal Cushing syndrome, restoration of the suppressedhypothalamic pituitary adrenal (HPA) axis was observed in half of thecases, even in patients with severe Cushing syndrome who had previouslybeen treated with metyrapone chronically. Restoration of the HPA axis,based on recovery of the ACTH secretion and in some cases restoration ofthe diurnal cortisol rhythm, was observed within 2 to 6 weeks oftreatment with relacorilant. This is an important finding, and bearsemphasis for at least two reasons: A) It shows the rapid beneficialeffects of relacorilant in patients with cortisol excess. The recoveryof the HPA axis following curative surgery typically takes severalmonths and sometimes takes years; and B) It provides a marker for dosetitration in a manner analogous to thyroid-stimulation hormone (TSH) inpatients with hyperthyroidism or plasma renin activity in patients withprimary aldosteronism.

The safety profile of relacorilant in patients with endogenous Cushingsyndrome was also significantly better than that seen with mifepristone.Unlike mifepristone's adverse events related to progesterone receptorantagonism, no cases of drug induced vaginal bleeding were seen in therelacorilant study, even among patients who had previously developedvaginal bleeding while taking mifepristone. Equally important, nopatients developed drug induced hypokalemia, even those who haddeveloped hypokalemia while taking mifepristone. The most commontreatment-emergent adverse events (TEAEs) were back pain, edema,headache, and nausea.

In the Phase 2 CORT125134-451 study with relacorilant, five patientsbeing treated with other approved medical therapies were titrated offtheir medication and enrolled in the study. These patients had onlypartially responded or had developed adverse events to the othertherapies. Two patients had been treated with metyrapone, two withketoconazole and one with mifepristone. In both patients treatedpreviously with metyrapone, relacorilant showed higher efficacy based onimprovement in the primary endpoints, improved glucose control andhypertension, and secondary end points, including weight loss andrecovery of the HPA axis. The patient who was treated previously withmifepristone had developed endometrial hypertrophy which completelyresolved during treatment with relacorilant.

Relacorilant was rationally designed to be a selective GR antagonist anddoes not bind to other nuclear steroid hormone receptors. Relacorilant'sGR selectivity and particularly its lack of binding to the progesteronereceptor provides a significant safety advantage over mifepristone.There have been no reported instances with relacorilant to date of twocommon TEAS reported with mifepristone: vaginal bleeding or hypokalemia.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it will be readily apparent to those of ordinary skill inthe art in light of the teachings of this invention that certain changesand modifications may be made thereto without departing from the spiritor scope of the appended claims.

I claim:
 1. A method of treating a patient suffering from a symptom ofhypercortisolemia, or comorbidity thereof, the method comprisingadministering to the subject an effective amount of relacorilant,CORT122928, CORT113176, CORT125281, or CORT125329, effective to treatsaid symptom or comorbidity of hypercortisolemia, Wherein relacorilantis:(R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,which has the formula

wherein CORT122928 is:(R)-(1-(4-flurophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,termed, having the formula

Wherein CORT113176 is:(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,having the formula

Wherein CORT125281 is:((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanonewhich has the structure:

and Wherein CORT125329 is:((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,having the formula:

and wherein said symptom or comorbidity of hypercortisolemia is one ormore of: hyperglycemia, wherein said treatment is effective to lower thepatient's AUC_(glucose) by at least about 15% as compared to thepatient's baseline AUC_(glucose) measured prior to treatment;hypertension, wherein said treatment is effective to lower the patient's24-hour mean systolic or 24 hour mean diastolic blood pressure by atleast about 5 millimeters of mercury (mmHg) as compared to the patient'sbaseline blood pressure measured prior to treatment; an abnormal liverenzyme level, wherein said treatment is effective to lower an abnormalpatient liver enzyme level as compared to the patient's baseline liverenzyme level measured prior to treatment; an abnormal fructosaminelevel, wherein said treatment is effective to improve an abnormalpatient fructosamine level as compared to the patient's baselinefructosamine level measured prior to treatment; an abnormal serumosteocalcin level, wherein said treatment is effective to improve anabnormal patient serum osteocalcin level by at least 1 microgram perliter as compared to the patient's baseline serum osteocalcin levelmeasured prior to treatment; an abnormal heartbeat interval or medianheart rate, wherein said treatment is effective to improve an abnormalpatient heartbeat interval or median heart rate as compared to thepatient's baseline heartbeat interval or median heart rate measuredprior to treatment; an abnormal blood coagulation measure, wherein saidtreatment is effective to improve an abnormal patient blood coagulationmeasure as compared to the patient's baseline blood coagulation asmeasured prior to treatment; an abnormal blood cell measure, whereinsaid treatment is effective to improve an abnormal patient blood cellmeasure as compared to the patient's baseline blood cell measure asmeasured prior to treatment; an abnormal adrenocorticotropic hormone(ACTH) or pro-opiomelanocortin (POMC) level, wherein said treatment iseffective to improve an abnormal patient ACTH or POMC level as comparedto the patient's baseline ACTH or POMC level as measured prior totreatment; improve quality of life in a Cushing's patient, wherein saidtreatment is effective to improve patient quality of life as measured byCushing Quality of Life Score, as compared to the patient's baselinequality of life as so measured prior to treatment; improve cognition ina Cushing's patient, wherein said treatment is effective to improvepatient cognition as measured by a Trail Making cognitive test, ascompared to the patient's baseline cognition as measured by saidcognitive test prior to treatment; lessen patient depression, asmeasured by the Beck Depression Scale, wherein said treatment iseffective to reduce patient depression as indicated by the BeckDepression Scale as compared to the patient's baseline depression asmeasured prior to treatment; whereby the patient suffering fromhypercortisolemia and a symptom or comorbidity thereof is treated andthe symptom or comorbidity is improved.
 2. The method of claim 1,wherein said symptom or comorbidity thereof is hyperglycemia, whereinsaid treatment is effective to lower the patient's hemoglobin A1c(HbA1c) by at least about 0.5% as compared to the patient's baselineHbA1c measured prior to treatment.
 3. The method of claim 1, whereinsaid symptom or comorbidity thereof is hypertension, wherein saidtreatment is effective to lower the patient's 24-hour mean systolic or24 hour mean diastolic blood pressure by at least about 5 millimeters ofmercury (mmHg) as compared to the patient's baseline blood pressuremeasured prior to treatment.
 4. The method of claim 1, wherein saidsymptom or comorbidity thereof is an abnormal heartbeat interval ormedian heart rate, wherein said treatment is effective to improve anabnormal patient heartbeat QT interval or ECG median heart rate ascompared to the patient's baseline heartbeat QT interval or ECG medianheart rate measured prior to treatment.
 5. The method of claim 1,wherein said symptom or comorbidity thereof is an abnormal liver enzymelevel, wherein said treatment is effective to lower patient alanineaminotransferase (ALT) or aspartate aminotransferase (AST) liver enzymelevel, or both, as compared to the patient's baseline ALT or AST liverenzyme level measured prior to treatment.
 6. The method of claim 1,wherein said symptom or comorbidity thereof is an abnormal fructosaminelevel, wherein said treatment is effective to improve an abnormalpatient fructosamine level as compared to the patient's baselinefructosamine level measured prior to treatment.
 7. The method of claim1, wherein said symptom or comorbidity thereof is an abnormalosteocalcin level, wherein said treatment is effective to improve anabnormal patient osteocalcin level by at least 1 microgram per liter ascompared to the patient's baseline osteocalcin level measured prior totreatment.
 8. The method of claim 1, wherein said symptom or comorbiditythereof is an abnormal blood coagulation factor level, wherein saidtreatment is effective to improve an abnormal Factor IX or an abnormalFactor X level as compared to the patient's baseline Factor IX or FactorX level as measured prior to treatment.
 9. The method of claim 1,wherein said symptom or comorbidity thereof is an abnormal bloodcoagulation measure, wherein said treatment is effective to improve anabnormal thrombin-antithrombin (ATT) or an abnormal activated partialthromboplastin time (aPTT) as compared to the patient's baseline ATT oraPTT as measured prior to treatment.
 10. The method of claim 1, whereinsaid symptom or comorbidity thereof is an abnormal blood cell measureselected from an abnormal eosinophil measure or abnormal platelet count,wherein said treatment is effective to improve an abnormal patienteosinophil measure or abnormal platelet count as compared to thepatient's baseline eosinophil measure or abnormal platelet count asmeasured prior to treatment.
 11. The method of claim 1, wherein saidsymptom or comorbidity thereof is an abnormal adrenocorticotropichormone (ACTH) or pro-opiomelanocortin (POMC) level, wherein saidtreatment is effective to improve an abnormal patient ACTH or POMC levelas compared to the patient's baseline ACTH or POMC level as measuredprior to treatment.
 12. The method of claim 1, wherein said symptom orcomorbidity thereof is impaired quality of life in a Cushing's patient,wherein said treatment is effective to improve patient quality of lifeas measured by Cushing Quality of Life Score, as compared to thepatient's baseline quality of life as so measured prior to treatment.13. The method of claim 1, wherein said symptom or comorbidity thereofis impaired cognition in a Cushing's patient, wherein said treatment iseffective to improve patient cognition as measured by a Trail Makingcognitive test, as compared to the patient's baseline cognition asmeasured by said cognitive test prior to treatment.
 14. The method ofclaim 1, wherein said symptom or comorbidity thereof is depression, asmeasured by the Beck Depression Scale, wherein said treatment iseffective to reduce patient depression as indicated by the BeckDepression Scale as compared to the patient's baseline depression as someasured prior to treatment.
 15. The method of claim 2, wherein saidnonsteroidal selective glucocorticoid receptor modulator (selective GRM)is a heteroaryl-ketone fused azadecalin compound selected fromrelacorilant, CORT122928, and CORT113176.
 16. The method of claim 3,wherein said nonsteroidal selective glucocorticoid receptor modulator(selective GRM) is a heteroaryl-ketone fused azadecalin compoundselected from relacorilant, CORT122928, and CORT113176.
 17. The methodof claim 5, wherein said nonsteroidal selective glucocorticoid receptormodulator (selective GRM) is a heteroaryl-ketone fused azadecalincompound selected from relacorilant, CORT122928, and CORT113176.
 18. Themethod of claim 7, wherein said nonsteroidal selective glucocorticoidreceptor modulator (selective GRM) is a heteroaryl-ketone fusedazadecalin compound selected from relacorilant, CORT122928, andCORT113176.
 19. The method of claim 2, wherein said nonsteroidalselective glucocorticoid receptor modulator (selective GRM) is anoctandryo fused azadecalin compound selected from CORT125281, andCORT125329.
 20. The method of claim 3, wherein said nonsteroidalselective glucocorticoid receptor modulator (selective GRM) is anoctandryo fused azadecalin compound selected from CORT125281, andCORT125329.
 21. The method of claim 5, wherein said nonsteroidalselective glucocorticoid receptor modulator (selective GRM) is anoctandryo fused azadecalin compound selected from CORT125281, andCORT125329.
 22. The method of claim 7, wherein said nonsteroidalselective glucocorticoid receptor modulator (selective GRM) is anoctandryo fused azadecalin compound selected from CORT125281, andCORT125329.